3 s2.0 B9780323858526000019 Main

C H A P T E R
19
Herbal biomolecules: anticancer agents
Nagarjuna Reddy Desam1 and Abdul Jabbar Al-Rajab2
1
Anantha Lakshmi Institute of Technology & Sciences, Ananthapuram, India
2
Etcectera Publications, Chesterville, ON, Canada
19.1 Introduction worldwide [4], and the mortality rate in 2018

included 9.6 million deaths from cancer [4]. In
Cancer kills more than seven million people 2018, the incidence of cancer worldwide was
every year worldwide [1]. Medical advances in Asia (48.4%), Europe (23.4%), Americas
the last few decades, even in developed coun- (21.0%), Africa (5.8%), and Oceania (1.4%), and
tries, have not changed the impact of this dis- the mortality rates are Asia (57.3%), Europe
ease [1]. Cancer is one of the most catastrophic (20.3%), Americas (14.4%), Africa (7.3%), and
diseases, resulting in more deaths compared Oceania (0.7%) [4]. The globally estimated cancer
with other diseases like heart attack, kidney incidence and death rates are shown in Fig. 19.1.
failure, stroke, etc. [1]. Since 1991, cancer death Furthermore, the death rates and occurrence
rates are continuously registering and decreas- have been increasing because of different type of
ing death rates [1]. In developed and develop- cancers; for example, liver and lung cancer.
ing countries, cancer is one of the major causes Globally, in men, the most common cancers are
of death [2]. In 2010, cancer costed the United liver, lung, colorectal, stomach, and prostate,
States economy around $1.16 million [3]. By while in women, breast, lung, cervical, colorectal,
2040, the number of new cancer cases per year and thyroid cancers are most common. Cancer is
is anticipated to rise to more than 27.5 million the unrestrained procreation of normal cells, pro-
[4]. In the United States alone, 21 million new ducing genetic unpredictability and modification
cases are expected annually by 2030 [5,6]. within tissues and cells. In cancer, normal cells
Worldwide, about 18.1 million new cases and convert into malignant cells. Genetic uncertainty
9.6 million cancer deaths were reported in incorporates mutations in deoxyribonucleic acid
2018, comprised of 8.8 million male (52%) and (DNA) repair genes, tumor suppressor genes
8.2 million female (48%) deaths, giving a and oncogenes, and genes required for cell
malefemale ratio of 10:9.3 [4]. According to extension metabolism. Many factors can cause
the world age-standardized rate (ASR), 204.7 cancer, including internal and external factors.
cases occur for every 100,000 men, and 175.6 External factors include pollutants in drinking
cases occur for every 100,000 females water, air, food, specific metals, chemicals,
Herbal Biomolecules in Healthcare Applications

DOI: https://doi.org/10.1016/B978-0-323-85852-6.00001-9 435 © 2022 Elsevier Inc. All rights reserved.
436 19. Herbal biomolecules: anticancer agents
TABLE 19.1 Different forms of top most organ based

cancer (male and female) estimated new cases by 2019
and estimated by 2030 in United States of America.
Estimated new Estimated new
cancer cases in cancer cases in
Type of cancer 2019 2030
Prostate 36,50,030 50,17,810

FIGURE 19.1 Estimated number of incident cases both Breast 38,61,520 49,57,960
(men and women) all cancers including nonmelanoma skin
cancer, for all ages, worldwide. melanoma of 13,56,610 1825720
the skin
tobacco, smoking, radiation, and infectious Colon & rectum 15,44,770 1959800
agents, while the body’s immune system, hor- Uterine corpus 8,07,860 10,23,290
monal disorders, and genetic mutations are inter-
nal factors. Among human beings, several types Thyroid 7,05,050 9,89,340
of cancer diseases occur; among these, the top Non-Hodgkin 7,57,720 10,16,560
listed cancer in males is lung cancer and breast lymphoma
cancer in females Table 19.1 [7], details the top Urinary bladder 6,24,490 8,32,910
most cancer incidences in 2019, followed by the
Lung & 5,71,340 7,24,610
estimated new cancer incidences by 2030 for bronchus
the United States. In developing countries, more
than 70% of deaths are due to cancer, and only Kidney & renal 5,69,570 7,93,530
pelvis
one in five countries provide essential data for
adequate cancer policies [3,5]. Improving the Testis 2,87,780 3,61,690
combat against cancer requires investment in Uterine cervix 2,83,120 2,88,710
cancer pathology research to develop anticancer
Leukemia 2,56,790 3,52,900
agents that are economical, safe, and have mini-
mal side effects. Oral cavity & 2,49,330 3,15,750
Cancer is an acute metabolic syndrome disease; pharynx
the fight against cancer requires diagnosis, treat- Ovary 2,49,230 2,97,580
ment, and prevention [58]. For many years,
herbal biomolecules (HBs), such as small organic
molecules derived naturally from microbes and
plants, have provided several useful cancer drugs. (secondary metabolites) have been used for the
HBs or natural products (NPs) play an important treatment of cancer. Worldwide, more than 3000
role in cancer prevention and treatment. About plants have been described with properties that
40% of HBs or NPs are accepted by the Food and support anticancer activity [5,6]. While current
Drug Administration (FDA), and among the 40%, studies in moderate-income and highly-populous
74% have been used as cancer therapy. Hence countries tend to ignore traditional medicines,
HBs are contemplated as less toxic and safer, and worldwide, HBs are commonly used for oncol-
biologically friendly for normal cells. ogy treatment. In developing countries, herbal
Globally, Indigenous cultures have used tradi- medicines have also been widely used in the last
tional herbal medicine for the treatment of lyso- few decades [814]. Evidence for HBs in cancer
somal storage disorders (LSDs) and myriad treatment has accumulated and gradually
maladies. In several countries, herbal molecules attracted increasing attention because they are

19.2 Cancer: plant-based treatment 437
safer to use and biologically more friendly, less antioxidant, antiinflammatory, and anticancer
toxic to the normal cells, and therefore coexist activity) such as ephedrine, morphine, and vinblas-
with their target sites [15]. Furthermore, evidence tine, which have been used for the treatment of
supports the use of NPs in anticancer drugs and asthma, pain, and cancer, respectively. A few alka-
for alternative modes of promoting cell death loids have been successfully isolated, developed,
[16,17]. Hence, many researchers are concentrat- and implemented as cancer drugs for chemother-
ing on plant sources of HBs that could be helpful apy; for instance, vinblastine, topoisomerase
to the pharmaceutical industry [1820] to (Topl), and camptothecin (CPT). Along with alka-
develop and discover drugs. About 49% of small loids, other HBs (terpenoids, polyphenols, flavo-
herbal molecules investigated have been accepted noids, etc.) showed potential biological activity.
for the treatment of cancer from 1940 to 2014 [21]. Worldwide, both developed and developing coun-
Worldwide, between 1981 and 2017, about 134 tries have used traditional medicinal plants as a
drugs to treat cancer have been recorded, among whole or their phytochemicals and derivatives fre-
which 17% are synthetic cancer drugs, and 83% quently [24,25]. This chapter deals with HBs and
are anticancer drugs from HBs or NPs. Among their importance for cancer treatment.
NPs or HBs, paclitaxel is a well-known antineo-
plastic drug used for the treatment of cancer
(breast cancer). It is extracted and isolated from 19.2 Cancer: plant-based treatment
Taxus brevifolia plant bark [22].
In recent years, some HBs or secondary meta- Since ancient times, various plant materials
bolites, such as alkaloids, terpenoids, flavonoids, have been used for traditional medicine; a
and polyphenols, have been shown to have poten- 5000-year-old Sumerian clay slab referencing
tial anticancer activity. For example, HBs have plant material used as medicine has been found
been extracted from various plants, including cur- near Nagpur, India. The clay slab refers to
cumin (Curcuma longa), vincristine (Catharanthus twelve drug recipes containing references to 250
roseus), paclitaxel (T. brevifolia), homoharringtonine plants [1]. Poppy, mandrake, and henbane are
(Cephalotaxus harringtonii and Cephalotaxus fortu- still used as therapeutics [26,27]. Around 2500
nei), ingenol mebutate (Euphorbia peplus), betulinic BCE, Emperor Shen Nung in China was
acid (Gratiola officinalis, Betula spp., Platanus instructed about traditional medicine from plants
acerifolia, Diospyros spp., Sarracenia flava, Ziziphus [28], and “the father of botany” (Theophrastus,
spp., and Syzygium spp.) [23]. HBs are a mixture c.300 BCE) established botanical science, docu-
of chemical composition, such as alkaloids, flavo- mented in his book “De Causis Plantarum.” In
noids, terpenoids, polyphenols, and essential oils this book, Theophrastus classified several medic-
(small organic molecules). For instance, among all inal plants [29,30]. Additionally, the importance
phytochemical constituents, alkaloids show of medicinal plants and their uses were incorpo-
potential biological activity. Alkaloids are com- rated in “De Materia Medica” (five- volumes) [31].
prised of cyclic carbon rings and nitrogen inside Theophrastus’ credentials were widely recog-
the ring structure and an extremely wide group nized, and later, he was recruited as a physician
of heterocyclic chemical constituents [23]. In the for the Roman army. Further studies of medici-
plant kingdom, alkaloids have a broad distribu- nal plants study were carried out in the Islamic
tion, including plants belonging to the golden age and in the Roman Empire. For exam-
Loganiaceae, Ranunculaceae, Menispermaceae, ple, the Islamic scholar Ibn Baitar’s book “Liber
Pepaveraceae, and Leguminosae families [23]. Magne Collections Simplicum Alimentorum Et
Furthermore, many alkaloids show potential bio- Medicamentorum” included thousands of medici-
logical activity (such as antibacterial, antifungal, nal plants [32]. At the dawn of modern

classification, Carl Linnaeus identified numerous NPs, especially the secondary metabolites or
plant species in his book, “Species Plantarum” HBs. HBs are small organic substances pro-
[33]. duced by an organism. These molecules are
In the early 19th century, with the develop- involved in plant development, growth, and
ment of advanced synthetic chemistry isolation, reproduction. HBs are structurally complex in
identification of active HBs or secondary metabo- nature, and at this time, it is difficult to achieve
lites and synthesis of active HBs from admired complete synthesis and show their wide area
medicinal plants such as pomegranate, poppy, of biological activity together with anticancer
quinine, and strychnos, etc., occurred [34]. Even activity [95,96]. Based on plants’ biosynthesis
with the early success of medicinal plant pathways, HBs are broadly classified. The most
research, little progress was made in the late 19th straightforward classification is into three main
and throughout the 20th century. The focus of groups: phenols, terpenoids, and alkaloids.
pharmaceutical industries shifted to synthetic These three main groups are biosynthesized in
chemistry and drug development [35]. However, different pathways. For instance, various alka-
in recent years, plant-based research has shifted loids have been biosynthesized from amino
to another level. In 2015, the Nobel Prize was acids and nonprotein nitrogen-containing com-
awarded to Tu Youyou (physiology and medi- pounds like tyrosine, which has been long
cine) for the discovery of the antimalarial drug medication history. Terpenoids are biosynthe-
artemisinin and its metabolite, dihydroartemisi- sized from polyisoprene derivatives as well as
nin. Hence, plant-based secondary metabolites acetate via the mevalonic acid pathway, and
are major and essential sources for drug discov- phenols are biosynthesized with one or more
ery. In view of the success of developing this hydroxylated benzene rings from the shikimate
antimalarial drug, the National Cancer Institute pathway [97,98]. Every year, many HBs are iso-
(NCI) initiated a project Cancer moonshot aimed lated from plants, and their chemical constitu-
at seeking plant-based HBs as therapeutic agents ents provide more opportunities to investigate
against cancer. The goal of the project was to biological properties, including treatment of
develop more therapeutic agents as well as focus cancerous diseases.
on HBs and phytochemicals. As a result of Recently, several medicinal plants have been
this project, NPs and phytochemical components recognized with significant anticancer activity
have been stored and purified and are available [99,100], and HBs have been isolated from
for researchers to develop new anticancer agents. them. For example, anticancer medicines like
Currently, thousands of potential anticancer vinblastine, vincristine and vindesine have been
plant-based phytochemicals have been reported, used as chemotherapeutic agents for the treat-
and among them, a good number of HBs or phy- ment of cancer like lung, breast, lymphomas,
tochemicals have been clinically successful. For Kaposi’s sarcoma, and leukemias [42,99,100]
example, some of the plant-based HBs or plant after being isolated from Madagascar periwinkle
chemical constituents as potential anticancer and C. roseus (Apocynaceae) plants. Another
agents given in Table 19.2. cancer drug, paclitaxel (Taxol), was discovered
by the American native tribes, isolated from T.
brevifolia Nutt (Pacific Yew), T. canadensis and T.
19.3 Plants secondary metabolites as baccata L. plants. Taxol has been used for the
anticancer drugs treatment of breast and ovarian cancer [42,99].
Homoharringtonine, a potential cancer drug,
Throughout history, traditional herbal has been extracted from the (cephalotaxaceae)
plants have been sources of abundant HBs or Cephalataxus harringtonia (Chinese tree) and

19.3 Plants secondary metabolites as anticancer drugs 439
TABLE 19.2 Important herbal medicinal plants, phytochemicals, source and its cancer activity.
Scientific name Phytochemical Cancer activity References
Artemisia annua Artemisinin Liver, breast, and pancreatic cancer [36]

Andrographis paniculata Andrographolide Colon cancer [37]
Amoora rohituka Amooranin Lymphocytic leukemia [38]
Centella asiatica Asiatic acid Melanoma, glioblastoma, breast cancer [39]
Actaea racemosa Actein Liver and breast cancer [40]
Allium sativum Allin Carcinoma of human mammary gland [29]
Matricaria chamomilla Apigenin Colorectal cancer [41]

Betula Sp., Ziziphus rugosa, Betulinic acid Human melanoma xenografts and leukemia [4244]
Betula utilis
Boswellia serrata Boswellic acid Prostate cancer [45]
Bryophyllum pinnatum Bryophyllin A Cervical cancer [46]
Annona squamosa Bullatacin Liver cancer [47]
Colchicum autumnale Colchicine Multiple solid tumors [48]
Taxus baccata Cabazitaxel Prostate cancer [49]
Colchicum autumnale Colchicine Hodgkin’s lymphoma, chronic granulocytic leukemia [50]

Curcuma longa Curcumin Colon adenocarcinoma [51,52]
Breast, lung, prostate esophagus, liver, and skin cancer
Passiflora caerulea Chrysin Colorectal cancer [53]

Combretum caffrum Combretastatins Colon, leukemia, and lung cancer [54]
Cannabis sativa Cannabinoid Lung, pancreas, breast, prostate, and colorectal cancer [55]
Vitis vinifera Cyanidin Colon cancer [56]
Calvatia caelata Calcaelin Breast and spleen cancer cells [57]
Morinda citrifolia Damnacanthal Lung cancer, sarcomas [58]
Withania somnifera 5-Fluorouracil Human cervical cancer cell [59]

Leea indica Gallic acid Ehrlich ascites carcinoma [60]
Gossypium hirsutum Gossypol Breast, stomach, liver, prostate, Colorectal and bladder [61,62]
cancer
Z. officinale Ginger Ovary, cervix, colon, liver, and urinary caner [63]
Peganum harmala Harmine Breast cancer [64]
Glycyrrhiza uralensis Isoliquiritigenin Human lung cancer [65]
Bauhinia variegata Kaempferol Breast, lung, and liver cancer [66]
galactoside
(Continued)

TABLE 19.2 (Continued)

T. baccata Larotaxel Breast, bladder, and pancreatic cancer [67]

Capsicum annuum Luteolin Colorectal cancer [37]
Solanum lycopersicum Lycopene Prostate and colon cancer [68]
Lentinus edodes Lentinan Sarcoma-180 in mice [69]
Nelumbo nucifera Neferine Liver cancer [70]
T. brevifolia nab-paclitaxel Ovarian and breast cancer [71]
Moringa oliefera Niazinine A Blood cancer [72]

T. brevifolia Paclitaxel Breast and ovarian cancer [42]
Psoralea corylifolia Psoralidin Stomach and prostate cancer [73]
Podophyllum peltatum Podophyllotoxin Non-small-cell lung carcinoma [74,75]
Podophyllum hexandrum Breast, ovary, lung, liver, bladder, and testis cancer
Panax ginseng Panaxadiol Human colon cancer [76]
Plumbago zeylanica Plumbagin Blood, skin, liver, fibrosarcoma, leukemia, and breast [77,78]
cancer
Boerrhavia diffusa Punarnavine Malignant melanoma cancer [79]
Vitis vinifera Procyanidins Human colon cancer [80]
Polygonum cuspidatum Resveratrol Colorectal, skin, and liver cancer [81]
Solanum nigrum Solamargine Breast, liver, lung, and skin cancer [82]
Saffron crocus Saffron Liver, lung cancer and pancreatic cancer [83]
Schizophyllum commune Schizophyllan Head and neck cancer [84]
Sylibum marianum Silymarin Colorectal cancer and colon cancer [85,86]
S. marianum Silibinin Lung, liver, skin, colon, and prostate cancer [87]
Aegle marmelos Skimmianine Liver cancer [88]
Zingiber officinale 6-Shogaol Ovary cancer [89]

Tylophora indica Tylophorine Breast cancer [54]
Nigella sativa Thymoquinone Colon, prostate, breast, and pancreas cancer [66]
Camellia sinensis Theabrownin Lung cancer [90]
Debregeasia saeneb Tannins Internal tumors [9]
Oldenlandia diffusa Ursolic acid Lungs, ovary, uterus, stomach, liver, colon, rectum, [91]
and brain cancer
Vitex agnus-castu Vitex Human uterine, ovarian, cervical, and breast cancer [92]
(Continued)

19.4 Plant collection, extraction, identification, and anticancer a activity of HBs 441
Catharanthus roseus Vincristine Lymphocytic leukemia [42]

Vinblastine Leukemias, testicular, breast and lung cancer
Vindesine
Withania somnifera Withaferin A, D Breast, cervix, prostate, and colon cancer [93]
Xanthium strumarium Xanthatin Lymphocytic leukemia and liver cancer [94]
Ficus drupacea. Homoharringtonine has been room temperature and water molecules
used successfully for the treatment of myeloge- removed from the extracts using anhydrous
nous leukemia. Another potential cancer drug, sodium sulfate. The extracts were stored in a
ellipticine, was extracted and isolated from refrigerator at 4 C for further purposes, like the
Bleekeria vitensis A. C. Sm. It is used successfully investigation of chemical composition (alka-
for the treatment of breast cancer [42,99101]. loids, terpenoids, tannins, flavonoids, phenols,
These are some of the successful stories repre- and carbohydrates, etc.) using phytochemical
senting plant-based compounds as anticancer screening tests. Further, without isolation of
agents with the potential to find more in the individual chemical constituents, the % compo-
near future [42,99]. sition, molecular weight, and molecular formula
can be determined using chromatographic and
spectroscopic methods aimed at structural eluci-
dation. Gas chromatography-mass spectrometry
19.4 Plant collection, extraction, (GC-Ms), liquid chromatography-mass spec-
identification, and anticancer a activity of trometry (LC-Ms), and LC-nuclear magnetic res-
HBs onance (NMR) spectroscopy have been useful
for the interpretation and classification of NPs.
Plants are generally identified, dried under Biological properties of crude extracts, including
shade (without degradation of chemical com- antibacterial, antifungal, antivirus, antiinflam-
pounds), made fine-powdered, and extracted matory, antioxidant, and anticancer activity,
using various methods, such as continuous etc., have been investigated, and they can be
and noncontinuous extraction methods. For further isolated into individual chemical consti-
instance, continuous extraction includes macer- tutes for structural elucidation by spectroscopic
ation, percolation solvent extraction and soxhlet methods. These plant-based crude extracts, as
extraction, hydro distillation, and steam distilla- well as individual chemical constituents, have
tion; decoction, reflux extraction, pressurized been tested in vitro and in vivo for anticancer
liquid extraction, supercritical fluid extraction, activity. In vitro models include trypan blue
ultrasound-assisted extraction, pulsed electric dye exclusion assay, lactose dehydrogenase
field extraction and enzyme-assisted extraction assay (LDH), mean transit time (MTT) assay,
are considered as noncontinuous or short-time cell proliferation kit (XTT) assay and sulforho-
extraction methods of plant-based chemical damine B assay, and induction of Ehrlich ascites
compounds. From these extracts, solvents are carcinoma in in vivo models has been used for
removed by the rotary evaporator method at screening anticancer activity [102].

19.5 Modern drugs for cancer treatment There is also a very important limitation: cancer
and its limitations cells could become resistant to the chemothera-
peutic drugs as they go through mutations. For
A large number of cancer drugs are currently instance, with docetaxel applied against cancer,
used for cancer treatment; however, many drug resistance genes (ABCA4 and ABCA12)
induce significant side effects. To reduce the side were over-expressed in human MCF-7 breast
effects on the nearby cells, tissues and drug accu- cancer cells, respectively. When, instead of doce-
mulation and success in the injury advance, new taxel, curcumin (phytochemical) was used for
drug delivery and targeting systems are required cancer treatment, a resultant decrease of the
[103]. Methods for the treatment of cancer drug resistance genes has been noticed [108].
include chemotherapy, radiotherapy, surgery, Consequently, for the treatment of cancer, a sin-
vaccination, cell transformation, immunotherapy; gle targeted chemotherapeutic agent is not a suc-
therapies frequently interact to cause severe side cessful method. Hence, based on substantial
effects [104,105]. Cancer treatment is based research, plant-based HBs and their derivatives
on the type of cancer, stage, and location. show fewer toxic effects and provide a better
Chemotherapeutic drugs affect cytostatic and treatment for cancer [109].
cytotoxic conditions, showing encouraging
results singly or in combination with further can-
cer treatment. Chemotherapeutic drugs can 19.6 Present cancer therapy via
cause several side effects. For instance, irinotecan phytochemicals: as a novel approach
has been used for the treatment of topoisomerase
inhibition; it causes side effects, including diar- Traditional herbal medicinal plants are God’s
rhea, neutropenia, and sensor neuropathy. gift to nature and to serve human health. Since
Doxorubicin, alkylating agents (including mel- ancient times, plant-based HBs and their ana-
phalan, cisplatin, oxaliplatin and cyclophospha- logs have been used for medicinal practices.
mide), and microtubule agents (including Taxol, Various herbal medicinal plants, HBs, and their
vinblastine, docetaxel and vincristine) cause derivatives have been inhibiting cancer growth
potential side effects such as cardiotoxicity, and propagation [108]. The plant kingdom
hematologic toxicity, gastrointestinal toxicity, encompasses around 250,000 species, and about
nephrotoxicity, cardiovascular, and pulmonary 10% of plants have been studied for the treat-
toxicity, etc., [106,107]. These chemotherapeutic ment of various diseases. Various parts from
drugs have been used for a broad range of can- plants show different HBs or phytochemical
cer treatments, but these drugs are commercially constituents; for example, leaf, bark, roots, rhi-
very expensive, quite toxic, highly complex, and zomes, stem, fruits, seeds, flowers, flower stig-
not environmentally friendly. In the human mas, sprouts, and pericarp carry out various
body, under normal physiological ambience, a pharmacological functions. Various phytochem-
few cells multiply rapidly, such as digestive cells, ical constituents from plants like flavonoids, ter-
hair follicles, and bone marrow cells, etc.; hence, penoids saponins, tannins, taxanes, minerals,
the present chemotherapeutic drugs also damage gums, oils, glycosides lignans, HBs and primary
normal cells, which is a source of many side and secondary metabolites show potential for
effects. Detrimental side effects, including hair inhibiting cancer cell operating proteins, signal-
loss, heart disease, decreased blood production, ing pathways, and enzymes (Fig. 19.2A) or by
nervous disorders, gastrointestinal (GIT) inflam- operating DNA repair mechanisms, Bax, Bid,
mation, and immunosuppression, etc., may arise. Bak proteins and enzymes, and antioxidant,

19.7 Herbal biomolecules with anticancer activity 443
and anticancer effects in terms of their success 19.7 Herbal biomolecules with
on proteins, enzymes and signaling pathways anticancer activity
(Fig. 19.2B) [9].
A survey of herbal medicinal plants, NPs, and
HBs and their derivatives shows significant anti-
cancer activity. NPs or HBs are naturally
sourced. The plant-based chemical constituents
are composed of primary and secondary metabo-
lites and their derivatives. Primary metabolites,
including alcohols, and amino acids, etc., show
significant anticancer activity, as shown in
FIGURE 19.2 (A) impact of anticancer herbal biomole- Table 19.3. Secondary metabolites, including phe-
cules after activating expression of enzymes, genes, signal nols, flavonoids, alkaloids, and terpenoids, are
cascade and proteins in order to block cancer initiation and compiled and other NPs are naturally sourced
progression. (B) impact of anticancer herbal biomolecules
after inhibiting expression of enzymes, genes, signal cas-
from animals, microorganisms, vitamins, etc.;
cade, and proteins in order to block cancer initiation and hence, secondary metabolites show significant
progression. anticancer activity.
TABLE 19.3 Natural products (primary metabolites) anticancer activity.

Source of the plant Family Phytochemical Specific cancer suppressed References
Abrus recatorius Fabaceae Abrin Colon cancer [110,111]

Allium sativum Alliaceae Ajoene Leukemia, skin basil cancer [112,113]
A. sativum Alliaceae Allicin Colon, cervical cancer [114116]
Brassica spp. Brassicaceae Phenyl Human pancreatic cancer [117119]
isothiocyanate
Allium spp. Alliaceae Dially disulphide Cervical cancer [120122]
Allium spp. Alliaceae Dimethyl disulfide Colon cancer cell [123,124]

Jasminum spp. Oleaceae Jasmonic acid [125]
Carthamus tinctorius Asteraceae Linoleic acid Prostate cancer, scirrhous gastric cancer [126]
Perilla frutescens Lamiaceae Linoleic acid Prostate cancer, scirrhous gastric cancer [127]
Mimosa spp., Fabaceae L-Mimosine Human malignant melanoma, human osteosarcoma [128,129]
Leucaena spp. cells, lung cancer
Prunus cerasus Rosaceae Melatonin Breast cancer, Liver cancer [130,131]
Jasminum spp. Oleaceae Methyl jasmonate Leukemia, breast cancer [132,133]
Brassica spp. Brassicaceae Phenyl ethyl- Human pancreatic cancer cell [119]
isothiocyanate
Malus spp. Rosaceae Sorbitol Human erithro-leukemia cells, colorectal cancer [134,135]
Brassica spp. Brassicaceae Sulforaphane Human prostate cancer cells [136,137]

19.7.1 Phenols as anticancer activity lignans, neolignans ((C6-C3)2 skeleton; ex:

eusiderin, pinoresinol, etc.), biflavonoids
Phenols contain a wide class of NPs ((C6-C3-C6)2 skeleton; ex: Amentoflavone, lig-
obtained mainly from plants, in addition, to nins), condensed tannins ((C6-C3)n, (C6)n and
marine and microorganisms. Recent attentive- (C6-C3-C6)n skeleton; ex: phlobaphenes,
ness to these compounds has been increased proanthocyanidins) respectively. These phe-
significantly, due to their biological properties nolic compounds and their derivatives show
and various chemical structures. These phe- potential anticancer properties against differ-
nols could aid the prevention of persistent or ent cancers [138].
regressive diseases. Throughout the plant Cancer is currently a major public emer-
kingdom, phenols are broadly representing by gency; after cardiovascular diseases, cancer is
around 9000 various phenolic structures. the second major cause of death. Hence, several
Phenols have at least one aromatic ring and phenolic compounds have been tested for anti-
one or more hydroxyl groups attached, with cancer activity and continue to be potential
low to high molecular weights. These nor- leads. Phenolic compounds have been used for
mally appear as glycosides and esters. the treatment of malignant cancer. Some iso-
Phenols and their analogs are widely studied lated phenolic therapeutic agents, their natural
because of their valuable effects and different source, and their anticancer property are shown
relationships to human health. Today, more in Table 19.4. Among phenols, phenolic acids
than 60% of NPs or its analogs have been used are an important class of phenolic substances
as anticancer drugs; developing these active broadly present in the plant kingdom [201]
biomolecules is an optimistic prospect for the (Fig. 19.3). Phenolic acids comprise hydroxyben-
pharmaceutical industry, even as a model of zoic acids (e.g., gallic acid, vanillic acid, protoca-
finishing formulations of anticancer agents. techuic acid), hydroxycinnamic acids (e.g.,
The anticancer activity of the phenolic group caffeic acid, sinapic acid, ferulic acid, p-couma-
depends on the structure, including the aro- ric acid) [202]. Generally, phenolic acids are
matic ring and position of the hydroxyl group usually present in free or conjugated forms,
and nature of substituents on the benzene ring mostly present as amides and esters. Because of
[138]. Phenols consist of different classes of being structurally identical, various other phe-
molecule, including phenols and benzoqui- nolic acids are included as phenolic acids and
nones (C6 basic skeleton; ex: Catechol, hydro- their derivatives, like cynarine, ellagic acid, cap-
quinone, etc.), phenolic acids (C6-C1 skeleton; saicin, paradol, hydroxytyrosol (HXT), rosmari-
ex: salicylic acid and garlic acid, etc.), aceto- nic acid, gingerol, gossypol, and salvianolic acid
phenonones and phenylacetic acids (C6-C2 B [203,204]. Gallic acid, thyme, and clove are
skeleton; ex: p-hydroxyphenylacetic acid, substantially dietary and medicinal herbs, like
etc.), phenylpropenes, hydroxycinnamic acids, Cornus officinalis, Polygonum aviculare, Terminalia
coumarins, and isocoumarins (C6-C3 skeleton; chebula, Sanguisorba officinalis, Cassia auriculata,
ex: caffeic acid, eugenol, bergenin, ferulic acid Rheum officinalis and Rhus chinesis
and eugenin, etc.), naphthoquinones (C6-C4 [201,205207]. More hydroxybenzoic acids are
skeleton; ex: plumbagin and juglone, etc.), also included in medicinal and natural dietary
xanthones (C6-C1-C6 skeleton; ex: mangiferin, herbs (vegetables, fruits and spices).
etc.), anthraquinones, stilbenes (C6-C2-C6 skel- For instance, syringic acid, hydroxybenzoic
eton; ex: Resveratrol, emodin, etc.), flavo- acid, and protocatechuic acid are derived from
noids, isoflavonoids (C6-C3-C6 skeleton; ex: Saccharum elephantum officinarum and
Quercetin, genistein and cyanidin, etc.), Ceratostigma willmottianum, Dolichos biflorus,

TABLE 19.4 Phenolic substances with anticancer activity.
Phytochemical Natural source Type of cancer or carcinoma References
Aesculetin Aesculus hippocastanum Cervical [139]

Arbutin Arctostaphylos spp. Melanoma [140]
Acacetin Robiniapseudoacacia Gastric, breast [141,142]
Apigenin Petroselinum crispum Cervical [143]
Aloe emodin Rheum spp. Lung, nasopharyngeal [144]
Butein R. verniciflua Melanoma [145]
Baicalein S. baicalensis Prostate, gastric [146]

Chrysin Prunus spp Leukemia, hepatocellular [147]
Catechin A. catechu Melanoma, cervical, bladder, prostate, colorectal [148152]
Cyanidin Vaccinium spp Colorectal [153]
Cyanidin-3-glucoside Vaccinium spp. Lung [154]
Cyanidin-3-rutnoside Vaccinium spp. Lung [155]
Cuphiin D1 Cuphea hyssopifolia Leukemia, epidermoid, hepatocellular, [156]

prostate, cervical
Caffeic acid Cinnamomum verum Colon er [157]

Cajanol Cajanus cajan Breast [158]
Densiflorol B Bulbophyllum Leukemia, lung, hepatoma, stomach [159]
odoratissimum
Delphinidin Delphinium spp. Colorectal, prostate, leukemia [153]
Daidzein Glycine max Breast, prostate, colon [160]
Dicoumarol Dipteryx odorata Bladder, prostate [161]
Ellagic acid Vaccinium spp. Colon [162]
Epicatechin A. catechu Breast [163]
Epigallocatechin-3-gallate C. sinensis Leukemia, hepatoma, melanoma, breast, lung [164166]

Ferulic acid Ferula communis Skin, mammary [167,168]
Genistein Genista spp. Prostate, ovarian, cervical, bladder, breast [169171]
Garcinone E Garcinia mangostana Hepatocellular [172]
Gallic acid Kalanchoe spp. Leukemia, lung [173,174]
Hesperidin C. aurantium Nasopharyngeal [175,176]
Hesperetin Citrus spp. Breast [177]

Icariin Epimedium spp. Hepatoma [178]
Isoliquiritigenin G. glabra Melanoma [157]
(Continued)


Phytochemical Natural source Type of cancer or carcinoma References
Kaempferol Kaempferia galangal Hepato, pancreatic, osteosarcoma [179181]

Linariin Linaria vulgaris Large lung [182]
α-Mangostin G. mangostana Colon [183185]
Naringin C. aurantium Lung, gastric [186]
Naringenin Citrus spp. Colon [187]
Oenothein B Epilobium angustifolium Leukemia, epidermoid, hepatocellular, prostate, [156]
cervical
Psoralidin Psoralea corylifolia Cervical [188]
Phloretin Malus spp. Melanoma, hepatoma [189]

Peonidin-3-glucoside V. vinifera Lung cancer [190]
Protocatechuic acid Houttuynia cordata Colon, cervical [191]
Protoapigenone Thelypteris torresiana Breast [192]
p-Hydroxybenzoic acid Hypericum perforatum Colon, cervical [191]
Quercetin Citrus spp. Leukemia, gastric adeno, hepatocellular, lung, [192]
prostate, colon, breast
Resveratrol Vitis spp Leukemia, skin, breast, kidney, pancreatic, breast, [193]
prostate
Rhaponticin Rheum rhabarbarum Leukemia [194]
Rosmarinic acid Rosmarinus officinalis Colorectal [195]
Sinapic acid Brassica spp. Colon, cervical [191]

Syringic acid Ardisia elliptica Colon, cervical [142]
Toxifolin C. deodara Colon [186]
Vanillic acid A. sinensis Colon, cervical [191]
α-Viniferin B. odoratissimum Leukemia, submandibular gland [159]
Wogonin Scutellaria spp. Leukemia [196]
7-Hydroxycoumarin Hieracium pilosella Lung [197]

(umbelliferone)
7-Hydroxymatairesinol Picea abies Prostate [198]
(2)-Syringaresinol Castela emoryi Leukemia [199]

6-Hydroxyflavonone Colon carcinoma Barleria prionitis [186]
7,9,20 ,40 -Tetrahydroxy-8- S. flavescens Leukemia [200]
isopentenyl-5-
methoxychalcone

HO
OH
HO
HO
OH COOH
COOH COOH
medicinal and dietary plant spices, such as sage,
HO HO
Hydroxytyrosol
HO
p-coumaric acid
OH O mint, sweet basil, rosemary, and thyme, is used
Tyrosol Caffeic acid Ferulic acid
HO COOH
for potential antioxidant activity [205].
COOH COOH
O
COOH
HO COOH
HO HO
Polyphenolic aldehydes such as gossypol possess
HO HO OH
O
Sinapic acid
HO
Hydroxybenzoic acid Protocatechuic acid Gallic acid

O
Vanillic acid
cotton seeds, especially with Gossypium plants
O OH
(Malvaceae). It has been used for prophylactic
OH HO COOH OH
O COOH HO
OH O
activity and could cause potassium deficiency
OH HO OH
HO
O
HO O O
[204].
Syringic acid
O
Gossypol Rosmarinic acid
Medicinal herbs and dietary plants possess
HO
O
O
O OH O
O
phenolic substances, and these substances play a
OH N
HO
O
OH HO
H
OH significant role in the prevention of cancer. These
O
Ellagic acid Gingerol Capsaicin
substances’ mechanisms include free radical
O
O
COOH
OH
scavenging activity and antioxidant activity;
HO O OH
O OH OH inflection of mutagen metabolism; modulation of
HO O
O
OH
O O
OH
OH
HO HOOC
OH
OH
gene proclamation on oncogenes, and tumor
OH
HO
O
OH
OH HO
O O
OH
suppressor of genes in cell reproduction and dis-
HO
O O
Salvianolic acid Chlorogenic acid Cynarin1,3-dicaffeoylquinic acid

tinction; cell cycle apprehension and apoptosis;
obstruction of signal transduction pathways as
FIGURE 19.3 Herbal biomolecules of common phenolic well as nuclear factor activator protein-1 (AP-1),
acid and its derivatives from food sources and medicinal
herbs. mitogen-activated protein kinases (MAPK), acti-
vated B cells (NF-KB) and others; neuroprotective
effects on antiaging; enzyme detoxification, oxi-
Paeonia lactiflora and Feronia and grapes, star dation, and reduction; reproduction and transfor-
anise, dill, Cinnamomum cassia and Lawsonia iner- mation of vascular cells; antiinflammatory
mis, respectively. Various fruits, vegetables, properties; hormone metabolism and other bio-
grains, medicinal herbs, and dietary plants pos- logical effects; and activity on possible supple-
sess ferulic acid (present in wheat grain, wheat mental targets [203,204,212215].
bran), hyroxycinnamic acids (rich in red fruits Phenolic acids and their derivatives have a
such as strawberry, blueberry, blackberry, choke- wide range of biological properties; among them
berry, red raspberry, sour cherry, sweet cherry, a few phenolic substances could play important
red currant, and black currant). Ferulic acid, roles in prevention of cancer. Phenolic acids and
p-coumaric acid, ellagic acid, caffeic and p-hydro- their derivatives show free radical scavenging,
xybenzoic acid show potential anticancer and antioxidant, inhibition of tumor cells, inducing
antioxidant activity [208,209]. Caffeic acid is an cell cycle restrictions, increased detoxification,
ester of chlorogenic acids and enzymatic oxida- inhibition of a few enzymes, controlling signal
tion leading to sauté, extremely in potatoes and pathways, and other biological properties, includ-
apples. Chlorogenic acid is highly present in the ing antiviral, antiinflammatory, antibacterial, anti-
species of Asclepiadaceae and Apocyanaceae fungal, and antimutagenic activity [204,216219].
[210]. Radix salvia miltiorrhizae contains water- Garlic acid possesses antioxidant properties
soluble salvianolic acid B. It is used as a potential with significant repressive effects on cell repro-
antioxidant agent in China, and has been com- duction; it particularly showed cytotoxicity
mon in Chinese herbal medicine since ancient against tumor cells, which were more sensitive
times. Hydroxyphenolic acids liberate active than normal cells [220]. Ferulic acid, cinnamic
hydrogen to stop the lipid peroxidation reaction acid, and caffeic acid and their esters showed
[211]. Rosmarinic acid present in various herbal significant inhibition of the magnification of

fungi and bacteria, and HXT possesses antimyco- plants and include more than 4000 phenolic sub-
plasmal activity against Mycoplasma fermentans, stances [247]. Flavonoids’ carbon skeleton is gen-
Mycoplasma pneumonia, and Mycoplasma hominis erally C6-C3-C6, with a phenyl benzopyrone
[216]. Further, HXT has been shown to inhibit structure comprised of two aromatic rings
cell reproduction and the pursuit of lipoxy- (A and B rings) associated through three carbons;
genases (LOXs), enlarge catalase (CAT), decrease these are generally in an oxygenated central
vascular cell gluing molecule-1 (VCAM-1) pyran ring or C ring [201]. As per the unsatura-
mRNA and protein, decrease leukotriene B4 pro- tion and saturation level, the central pyran ring is
duction, moderate the lipid peroxidation process, open. Flavonoids are mainly classified into flavo-
decrease Fe21 and NO2, cause cytotoxicity, nols, flavanols, flavanones, flavones, anthocyna-
induce apoptosis by arresting the cells in the nins, chalones, bioflavonoids (including dimers
G0/G1 phase, and enhance superoxide dismu- of flavanones, flavones and flavonols), isoflavo-
tase (SOD) activity [221223]. Several phenolic noids, and neoflavonoids, as shown in Fig. 19.4.
acids and their derivatives, like HXT, gingerol, In medicinal herbs and dietary plants, flavonoids
cinnamic acid, paradol, and rosmarinic acid, pos- naturally occur in conjugated or free form. In
sess antiinflammatory effects as well as intensify plants, flavonoids are frequently in the form of
the immune function. Caffeic acids and chloro- glycosides along with sugar moieties linked with
genic acids possess in vitro toxic N-nitroso sub- hydroxyl (OH) groups (O-glycosides), as well as
stances and obstruct the development of between carbon-carbon bonds (C-glycosides).
mutagenic and antioxidant activity [204]; chloro- However, a few flavonoids are present as agly-
genic acid also obstructs the development of sin- cones [203,204]. Flavonoids are bound with more
gle stand DNA breaks as well as intercepts the than 80% of the various sugars; usually glyco-
formation of dinitrogen trioxide by searching for sides comprise glucoside, rhamnoside, galacto-
nitrogen dioxide generated in the human oral side, apiosylglucoside, malonyl, and glucoside
cavity [224]. In addition, capsaicin, caffeic acids, [248]. Dietary and medicinal herbs consisting of
and gingerol balance the ceramide-caused signal various types of flavonoids are especially repre-
transduction pathway, obstruct protein tyrosine sented. Dietary plants include vegetables, fruits,
kinase (PTK) activity, suppress the activation of and cereals. Flavonoids are a substantial class of
NF-KB and API [201,225,226], and [6]-gingerol phenol, and their derivatives are found in medici-
possesses an epidermal growth factor, and pro- nal herbs and dietary plants (Fig. 19.4)
duces tumor necrosis factor-alpha (TNF-α) and [201,202,205207,249]. The most important fla-
phorbol-12-myristate-13acetate (PMA)-induced vones include chrysin, apigenin, luteolin, and bai-
ornithine decarboxylase activity [225]. In addi- calein; their glycosides are predominately
tion, some phenolic acids extracted from grapes distributed in the Asteraceae and Labiatae fami-
and wine possesses significant activity against lies. For instance, flavones and their glycosides,
gastric, breast, and lung cancer [227]. Many phe- vitexin, baicalin, and apigetrin are extracted from
nols, phenolic acids, and their derivatives’ anti- Scutellaria baicalensis (roots), Chrysanthemun morifo-
cancer activities and mechanism are shown in lium (infloresences), and Artemisia annua (aerial
Table 19.5. parts), as well as dietary plants such as tea, cher-
ries, legumes, parsley, broccoli, and thyme, which
are major sources of flavones and its glycosides.
Kaempferol, galangin, and quercetin, and their
19.7.2 Flavonoids as anticancer agents glycosides (astragalin, rutin, and quecrcitrin) are
Flavonoids (phenols and their derivatives) nat- the major flavonols. These flavonols are found in
urally occur from medicinal herbs and dietary dietary plants, such as cumin, tea, red onions,

TABLE 19.5 Cancer prevention and its possible mechanism of phenols and its derivatives from dietary herbs and
medicinal plants.
Biological
properties Phenols and its derivatives Mechanism of action References
Antiangiogenesis Chlorogenic acid, HXT, apigenin, Inhibit cell proliferation; inhibit [203,204,215,228,229]
and daidzein, hesperetin, luteolin, oncogene expression; induce
antimutagenic myricetin, kaempferol, quercetin tumor suppressor gene
properties genistein, and silymarin, expression; inhibit vascular
daidzein, hesperetin, luteolin, endothelial growth factor.
kaempferol, myricetin, quercetin,
resveratrol, proanthocyanidins,
curcumin, coumarins, lignans,
quinones, and others.
Methoxylated flavonoids and DNA binding prevention [230,231]
flavones, (resveratrol, curcumin
and quinones).
Enzyme Chlorogenic acid, caffeic acid, Phase I enzyme (block activation [203,204,212,218,232235]
inhibition ellagic acid, HXT, apigenin, of carcinogens); COX-2; iNOS;
luteolin, quercetin, and EGCG, XO; signal transduction enzymes,
proanthocyanidins, corilagin, such as PKC and PTK;
resveratrol, apigenin, luteolin, topoisomerase I and II;
quercetin, and EGCG, coumarins, telomerase; urease; lipase;
proanthocyanidins curcumin, angiotensin I-converting enzyme;
podophyllotoxin, and quinones. DNA methytransferases
(consequent reactivation of key
tumor suppressor gene p16).
Enhancement of Cinnamic acids, rosmarinic acid, Suppress production of TNF, a [203,204,212,213,217,236,237]
immune HXT, gingerol, paradol, apigenin, pro-inflammatory cytokine and
functions and genistein, luteolin, quercetin, growth factor for most tumor
surveillance ECG, EGCG, silymarin, cells; suppress LOXs, iNOS,
proantho-cyanidins, tannic acid, chemokines, and other
resveratrol, curcumin, coumarin, inflammatory molecules.
sesamol, quinones, and others.
Enzyme Protocatechuic acid, ellagic acid, Phase II enzymes, such as UDP- [203,238,239]
induction and hesperidin, anthocyanins, glucuronosyl transferase and
enhancing tannins, quinine reductases; glutathione
detoxification resveratrol, curcumin, lignans, peroxidase; catalase; SOD;
and quinones. cytochrome P450 epoxide
hydrolase; NADPH:quinone
reductase.
Inhibition of cell HXT, baicalein, apigenin, Inhibit expression of cell- [203,221,222,240,241]

adhesion and flavonoids, resveratrol, curcumin, adhesion molecules, namely,
invasion and lignans. ICAM-1 and VCAM-1; inhibit
tumor cell invasion through
Matrigel, cell migration, and cell
proliferation.
Induction of cell differentiation [241,242]
(Continued)


Biological
properties Phenols and its derivatives Mechanism of action References
Apigenin, chebulinic acid, and

coumarins.
Inhibition of Caffeic acid, gallic acid, Inhibit formation of acrylamide [224,243]
acrylamide, homoorientin, luteolin, quercetin, and heterocyclic amines,
nitrosation, and EGCG, curcuminoids and others probable/possible human
nitration eugenol. carcinogens.
Regulation of Gossypol, isoflavones: Some are important [204,214,231,244]

steroid hormone formononetin, glycitein, phytoestrogens; modulate the
and estrogen genistein, daidzein, resveratrol, level of hormones; inhibit
metabolism coumestans: coumestrol, androgen receptor effects in
pinoresinol, lariciresinol, LNCaP prostate cancer cell.
secoisolariciresinol, and
matairesinol.
Inhibition of Caffeic acid, gingerol, capsaicin, Nrf-KEAP1 (Kelch-like ECH- [203,204,212,213,225,226,245,246]
signal apigenin, genistein, quercetin, associated protein 1) complex
transduction EGCG, and silymarin, signaling pathways; NF-κB and
pathways proanthocyanidins, curcumin, AP-1 signaling pathway,
ellagitannins, resveratrol, including c-Jun activity
esculetin, lignans, emodin, suppression; the Wnt or β-catenin
anethole and carnosol. signaling pathway (direct
inhibition of mitosis); MAPK
signaling pathway; growth-factor
receptor-medicated pathways.
Induction of cell- Ferulic acid, caffeic acid, ellagic Inhibit different cell cycles at [197,203,204,211,219,220,226]
cycle arrest and acid, HXT, quercetin, EGCG, different cell phases: G1, S, S/G2,
induction of gallotannin, proanthocyanidins, and G2; direct or indirect effect
apoptosis casuarinin, curcumin, resveratrol, on cell cycle arrest; subsequently
coumarin, sesamin, quinones 7- induce apoptosis, involving p53,
hydroxycoumarin, and others the Bcl-2, and caspase families.
eugenol.
ROS, reactive oxygen species; SOD, superoxide dismutase; TNF, tumor necrosis factor; LOX, lipoxygenases; iNOS, inducible nitric oxide
synthase; COX-2, cyclooxygenase-2; XO, xanthine oxidase; PKC, protein kinase C; PTK, protein tyrosine kinase; UDP, Uridine 5’-diphospho-
glucuronosyltransferase; NADPH, nicotinamide adenine dinucleotide phosphate; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular
cell adhesion molecule-1; Bcl-2, B-cell non-Hodgkin lymphoma-2; nuclear factor kappa of activated B cells; AP-1, activator protein-1; MAPK,
mitogenactivated protein kinases; LNCaP, lymph node carcinoma of the prostate; EGCG, epigallocatechin gallate; ECG, epicatechin gallate.
kale, apples, broccoli, tomato, berries, caraway, liquid refreshments (beverages). Generally, peo-
and wheat, as well as present in medicinal herbs ple from Western countries intake 2530 mg of
such as Sophoro japonica (flowers), Rosa chinensis flavonols daily. Flavanonols (e.g., naringenic,
(flowers), A. annua (aerial parts), Alpinia officinar- hesperetin, and liquiritin) and its glycosides (e.g.,
um (rhizomes) and Crataegus pinnatifida (fruits) naringin, and hesperidin) and flavanonols (e.g.,
[201,205]. Among flavonols, quercetin is one of taxifolin) are widespread in citrus fruits, includ-
the major dietary flavonoids. These flavonols are ing aurantium, oranges, and lemons, grapes, and
found in a wide range of vegetables, fruits and are also found in Leguminosae, Rutaceae, and

O O
O
O O Ginka biloba, Rhus succedanea and c. fruits
O
OH
O
OH
O
O
OH
O [201,251,252], and isoflavones and their glyco-
sides, such as formononetin, genistein, glycitein,
Flavonols Flavones Isoflavones Flavanonols Flavanones
HO
OH OH
OH HO
O OH O
OH
O
OH
O
OH
O
OH HO
daidzein, genistin, and daidzin mainly occur in
O
Flavanols Anthocyanidins
O
Chalcones
HO
-glucoside
HO
-galactoside
O OH red clover, soybeans and legumes, and are also
OH
OH
OH O HO O
OH
OH
OH identified in Astragalus mongholicus roots
O O
HO S
O
OH HO
OH
OH
OH O
-apiosylglucoside
[201,202].
-malonyl
OH
-glucoside -arabinoside
OH
Taxifolin
R
R1
R2
Flavonoids are connected to decreasing risk
OH OH OH
HO O HO HO O
OH
HO O
of extensive chronic diseases, including can-
OH
OH
OH O OH
OH OH O
R1=OH, R2=OCH3: hesperetin
cer. Hence, flavonoids show a strong free radi-
Catechin Butein R=H: epicatechin R1=H, R2=OH: naringenin
R2 R2
R=OH: epigallocatechin R1=OH, R2=OH: eriodictyol
R1
cal scavenging activity, including peroxyl
OH
HO O
R3
HO O
R1 R3
R4
HO O
R2
radicals, superoxide radicals, hydroxyl radi-
R1
OH O OH O
OH
OH
OH
cals, and hypochlorous acid; they also show
R1=H, R2=H, R3=H: chrysin
R1=H, R2=H, R3=OH : apigenin
R1=OH, R2=H, R3=H : baicalcin
R1=H, R2=H, R3=H, R4=H: galangin
R1=H, R2=H, R3=OH, R4=H: kacmpferol
R1=H, R2=OH, R3=OH, R4=H: quercetin
R1=H, R2=H:pelargonidin
R1=H, R2=OH:cyanidin
R1=OCH3, R2=H:peonidin
in vitro antioxidant activity [248]. Several fla-
R1=OH, R2=OH:delphinidin
OH
OH
O
OH vonoids react with transitional metal ions like
HO O
O
R
OH
HO O
O
O
copper and iron, reducing the potential to
OH OH OH
OH
O
R=H: epicatechin gallate OH
OH O
Silymarin
encourage reactive species formation. Like
R=OH: epigallocatechin gallate
phenol and its analogs, flavonoids also gener-

FIGURE 19.4 Chemical structures of major groups/ ate apoptosis by arresting the cell cycle, regu-
subgroups of flavonoids and its glycosides from medicinal
herbs and dietary plants. late multidrug resistance, stop dangerous
metabolic activation, inhibit proliferation or
reproduction of the angiogenic process, and
Rosaceae medicinal herbs [201,247]. Flavonols inhibit in vitro biomolecular damage by per-
also have been extensively identified in dietary oxynitrite [230,238,239,248]. These biological
and medicinal herbs. For example, catechin, epi- activities are related to their structures.
catechin, epicatechin gallate, epigallocatechin gal- Flavonols (e.g., rutin, myricetin, quercetin,
late (EGCG) and epigallocatechin are sourced and quercitrin) consist of many hydroxyl
from dietary plants such as berries, catechu, groups and demonstrate free radical scaveng-
cocoa, tea, and apples [203,247]. Prunella vulgaris ing activity and significant antioxidant activ-
(Inflorescences) and R. chinensis (flowers) possess ity. Flavanols also show potential antiradical
different type of anthocyanins and anthocyani- activity because of their catechol structure.
dins and their glycosides, including cyanidin, Several flavonoids have wide and different
pelargonidin, malvidin, peonidin, delphinidin, biological activities. For instance, apigenin
etc. [201]; anthocyanins are also found in food decreases the development of diolepoxide 2,
and dietary plants such as fruits, grains, vegeta- prostaglandin synthesis. Moreover, prevents
bles, corn, red cabbages, bayberry, grape skin, intercellular adhesion molecule-1 (ICAM-1),
beans, red rice, purple rice, blueberries, and pur- vascular cell adhesion molecule-1 (VCAM-1),
ple sweet potatoes [247,250]. Chalcones have inhibits cell adhesion and invasion, and
been identified in a few medicinal herbs, includ- induces cell differentiation and interferon-
ing Rhus verniciflua, Casthamus tinctorius, and gamma gene expression [240,242]. In addition,
Caesappinia sappan (e.g., butein, carthamin, phlore- quercetin, genistein, luteolin, EGCG, ECG,
tin, and sappanchalcone [201,202]). Bioflavonoids apigenin, and silymarin showed potential
are bound with a CaC or CaOaC bond [249]. antimutagenic properties, API, suppressed
These are naturally occurring in vegetables, fruits, the activation of NF-KB, stopped signal trans-
and medicinal herbs like Ouratea hexasperma, duction pathways, suppressed protein kinases

MAPKs, and prevented induction of apoptosis condensed tannins [201]. Tannins are a polyphe-
[225,226,240,242]. Excluding the above flavonol complex mixture. These are converted into
noids and their derivatives, myricetin, hesper- phenolic acids and sugars, which undergo a
etin, kaempferol, and daidzein were shown to change in pH or nonenzymatic or enzymatic
have antiinflammatory properties [204,253]. hydrolysis. The hydrolysable tannins are garlic
Furthermore, daidzein, genistein, and glyci- acid and its analogs. The general basic unit of
tein (soy isoflavone) show antitumor, preven- hydrolysable tannins is a polyester type [203].
tion of breast cancer, regulate steroid Hydrolysable tannins occur naturally together
hormone metabolism, and inhibit the growth with polysaccharides, proteins, and alkaloids
of new blood vessels and antiangiogenic activ- [204], and condensed tannins are structurally
ity [214,215]. more complex in nature, and they are more
Catechins, including EGCG and ECG, show broadly spread among the plants than hydroly-
potential antioxidant and free radical scavenging sable tannins. Condensed tannins are oligomers
activity. These substances chelate with transi- and polymers of flavan-3-diols known
tional metal ions such as copper and iron. as proanthocyanidins [255] and are also known
Hence, they do not generate any free radicals as leucoanthocyanidins (polymers of flavan-3,
[202]. EGCG could be able to reduce the appear- 4-diols) [202]. Naturally, tannins are major class
ance of cyclooxygenase (COX-2), p38 MAPK- of polyphenols. They are commonly found in
released signaling pathways, DNA methyltrans- medicinal herbs and dietary plants. Oligomeric
ferase, inhibit telomerase, increase nitric oxide condensed tannins are used for cancer treatment
synthase activity, moving of surrounding blood and healthcare and are powerful antioxidants.
CD8T cells, imposing cell growth G0/G1 phase These are commonly distributed in several fruits
of cell cycle, and LOXs [203,204,225,254]. such as apple, walnut, plum, olive, pomegranate,
Quercetin is one of the most significant antican- blackberry, raspberry, peach, longan, pine bark,
cer substances through its impact on the cell grape seed, and bark; they are also found in
cycle, oncogenes, protein kinases, telomerase, vegetables such as haricot beans, chick peas, and
antioncogenes, reducing lipoperoxidation, inhi- clove, cinnamon [256]. Gallotannis, ellagitannins,
biting the activity of caspases-3, increasing the and condensed tannins were found in around
appearance of nicotinamide adenine dinucleotide 112 Chinese medicinal plants (e.g., Chainese
phosphate (NADPH), protein expression, stages galls, S. officinalis, P. granatum and catechu) in 32
of oxidative metabolites, blocking lactate dehy- species [201]. In India, around 126 medicinal
drogenase (LDH) leakage, interacting with the plants possess hydrolysable tannins (e.g., R. suc-
β-catenin pathway, stopping c-jun N-terminal cedanea, Euphorbia hirta, and Glycyrrhiza glabra)
kinase (JNK) and colorectal crypt cell reproduc- [206]. Many ellagitannins, including colilagin
tion, and inducing different cell lines by arresting and casuariction, were identified and isolated
the cell cycle [203,204,226,232]. from dietary plants (fruits) such as Terminalla che-
bula (Combretaceae) and peels of pomegranate
(Lythraceae). Leucoanthocyanidins and
proanthocyanidins were found and isolated in
19.7.3 Tannins as anticancer activity Camellia sinensis (Theaceae) and Areca catechu
Tannins are considered as phenols, polyphe- (Arecaceae). Both hydrolysable and condensed
nolic compounds, and their derivatives; tannins tannins are found in P. granatum, Acacia catechu,
are soluble in water, having a molecular weight Rosa chinnesis and S. officinalis, etc. [201,202,206].
range from 500 to 4000. Tannins are broadly clas- Both condensed and hydrolysable tannins
sified into two classes: hydrolysable and show significant antioxidant and anticancer

HO
activity, because they have many hydroxyl O OH
OH O O
groups at different positions, but especially
more hydroxyl groups at the ortho position, HO HO OH
such as ortho-dihydroxyl or galloyl groups. trans-resveratrol

Curcumin
High molecular weight tannins possess high O

O OH
OH
galloyl or dihydroxyl groups at the ortho posi- O
tion, which shows strong anticancer activity O HO OH

[202]. Further, these tannins exhibit potential demethoxycurcumin
trans-pterostilbene
biological properties, such as antibacterial,
HO O OH
antiinflammatory, antimutagenic enzyme regu- OH O
lating, antiulcer, blocking signal transduction OH
HO OH
pathways, and apoptotic activities and other HO
biological activities. Hence, they have gener- trans-piceatannol bisdemethoxycurcumin
ated more interest and broad recognition for

Stilibenes Curcuminoids
cancer treatment Table 19.5 [219,233,245,257].
For instance, hydrolysable tannin, including FIGURE 19.5 Chemical structures of typical stilbenes
gallotannin has showed significant anticancer and curcuminoids from medicinal herbs and dietary
plants.
activity against colon cancer and Sweet Charlie
strawberries (which consist of hydrolysable
tannins) has been most successful at inhibiting dimeric, trimeric, and polymeric stilbenes or as
mutation [228]. Moreover, two chromone gal- glycosides. The most familiar chemical consti-
lates and four ellagitannins potentially occlude tuents such as phytoalexin and trans-
cuticular developing factor-induced cell migra- resveratrol rich in the human diet have trihy-
tion by reducing AP-1 and phosphoinositide droxystilbenes [204]. Monomeric and dimeric
3-kinase (PI3K) signaling pathways activation stilbenes are predominantly identified in
[245]. Chebulinic acid possess repressive result medicinal herbs. Especially trans-resveratrol,
on differentiation of human leukemia K562 piceatannol, and oxyresveratrol have been
cells along modulating transcriptional activa- identified and isolated from Polygonum cuspida-
tion of erythroid related genes, including tum (in roots), Polygonum multiflorum, P. lacti-
gamma-globin, NF-E2 genes and hemoglobin flora and Morus alba (in fruits) respectively.
synthesis [242]. Casuarinin is hydrolysable tan- [201,202]. Moreover, oligomers were identified
nin, identified and separated from Terminalia and isolated from Kobresia nepalensis, Hopea uti-
arjuna L. (Combretaceae), which inhibits repro- lis, Gnetum parvifolium, Shorea hemsleyana,
duction by blocking the cell cycle progression Vatica rassak, and Vatica indica [259]. Further
in the G0/G1 phase and by inducing apoptosis other stilbenes (astringin) have been identified
in human breast cancer cells [258]. recently in dietary plants. The above and other
stilbenes have been used as phytoestrogens to
protect against hormone-dependent tumors
[260].
19.7.4 Stilbenes as anticancer agents Among stilibenes, resveratrol particularly
Stilibenes are the derivatives of phenolic exhibits significant anticancer and antioxidant
substances, having ethane bounded with two activity and shows other biological properties
aromatic rings (Fig. 19.5) [203]. Stilbenes are such as antiviral, antibacterial, and antiinflamma-
broadly distributed in plants in the form of tory activities [203,204,225,226,244]. Since 1997,
monomeric (e.g., resveratrol, oxyresveratrol), the importance of resveratrol gradually increased,

and it has been used as an anticancer agent [260]. from various curcuma and zinger species includ-
Resveratrol would influence all three stages of ing Curcuma xanthorrhiza (from India), Curcuma
carcinogenesis, including tumor initiation, propa- domestica, Curcuma zedoaria (from Brazil) and
gation, and progression. Resveratrol and its Zingiber cassumunar (tropical regions) respec-
hydroxyl analogs show potent suppression of tively [206,262,263].
angiogenesis, metastasis, and regulation of sev- Curcuminoids and their analogs have been
eral pathways involved in cell development, used as chemotherapeutic agents in cancer
inflammation, antileishmanial, and apoptosis treatment and also have different biological
activity [229,261]. Resveratrol and its derivatives properties such as antiparasitic, antibacterial,
delay tumor progression by activating several antiviral, antiinflammatory antimutagenic,
intracellular pathways leading to cell growth antifibrosis, and antimicrobial activities
apprehension, like downplay of β-catenin expres- [231,241,264] (Table 19.5). In the extreme, cur-
sion; reprisal of reactive oxygen species (ROS) cumin could reduce proliferation, suppress
production; induction of mitochondrial biogene- tumor promotion and angiogenesis, reduce
sis; occlusion of NF-KB; API medicated signal oxidatively modified DNA, decrease magni-
transduce pathways; and inhibition of protein tude of NOS mRNA and protein, regulate AP-I
kinase C(PKC) activation [229,244,260,261]. In signal pathways, ensure degradation of IKB
addition, resveratrol could inhibit the lymph kinase β-activity, stop phosphorylation, inhibit
node carcinoma of the prostate (LNCaP) prostate NF-KB-modulate gene products, downregulate
cancer cell line [244]. Further, other stilbenes also iNOS expression, upregulate Map kinase
show potential inhibition against DNA topoisom- phosphate-5, support phosphorylation of JNK
erase II [259]. and p38 MAPK, support cytochrome release
and initiate caspase-8, BID cleavage, and pro-
mote proapoptotic and antimetastatic activities
[203,231,241]. In addition, colorless tetrahydro-
19.7.5 Curcuminoids as anticancer
curcuminoid shows significant anticancer
agents activity and is used in colorless food and cos-
Curcuminoids and their analogs are a class of metics. It also used for potent antioxidant
phenolic compounds. Ferulic acid and its deriva- activity [265]. Further, gingerol and its analogs
tives are known as curcuminoids, which consist in ginger possess strong antioxidant activity
of two ferulic acid structures connected with [225].
methylene with a β-diketone structure and
extremely conjugated system. Curcuminoids and
their derivate are naturally occurring from
19.7.6 Coumarins as anticancer activity
Zingiberaceae plant species [201]. These mainly
include curcumin, dimethoxycurcumin and bis- Coumarins are considered as phenolic com-
dimethoxycurcumin (Fig. 19.5) [202]. These pounds, which are obtained by cyclization of cis-
plants are mainly yellow in color like turmeric, ortho-hydroxycinnamic acid. The basic carbon
exceptionally to its rhizome [211]. C. longa skeleton of coumarins is considered as C6 1 C3
(Turmeric) and Zingiber officinale (ginger) consist (Fig. 19.6) [201]. These are generally formed
of curcuminoids and gingerol and its derivaties, through hydroxylation and isomerization of the
respectively [201]. These are mainly used in tra- trans-hydroxycinamic acid and its analogs. Plants
ditional herbal medicine, as natural color sub- are the major source of coumarins. These occur as
stances, and also as food source (spices) glycosides. Coumarins’ main chemical constitu-
everyday life [201]. Curcuminoids are isolated ents include simple hydroxylcoumarins,

HO O R
R
Murraya exotica and Toddalia aculeate; they are also
HO O O HO O O HO O O HO O O O O O
found in dietary plants like cumin and caraway
esculetin escopoletin scopoletin R=H: xanthyletin
R=Gluc: aesculin
R=OCH3:xanthoxyletin
OH
[205,206]. Moreover, from dietary plants (soya-
HO O O
O O O
HO
OH O
OH
beans) and medicinal plants (Pueraria mirifica),
O O O O
OH
OH
OH O O O
OH
HO
O coumarins and its derivatives have been identi-
O O OH
O
seselin khellactone psoralen bicoumarin
O
bergenin
O
fied and isolated, including coumestans, coumes-
O O O
OH
HO
OH
OH
HO
O O trol, and phytoestrogen, etc.
OH O HO
OH
Coumarins and its analogs exhibit signifi-
O O O
O O O
OH OH O cant anticancer activity, especially with
secoisolariciresinol matairesinol arctigenin
human cancer cell lines. For instance, cou-
wedelolactone
OH
O O O O O
O
O
O
O
O
O
O
O
O
O
O
O
O
marins and 7-hydroxycoumarin possess
O O
O O O O O O O O O
potential antitumor (in vitro and in vivo)
anhydropodorhizol
O O
morelensin
O
yatein
O
deoxypophyllotoxin
O
deoxypophyllotoxin
action against lung carcinoma cell lines by
OH inhibiting cell reproduction, blocking the cell
O O O
O
O
O
O
O O
OH
cycle in the G phase, and inducing apoptosis
O O
O O HO [197] (Table 19.5). Esculetin exhibits a signifi-

O O O
beta-peltatin
O
hinokinin
O O
sesamin
magnolol
cant inhibitory effect on the reproduction
response in vascular smooth muscle cells by
FIGURE 19.6 The chemical structures of common cou- regulating the P signal transduction pathway
marins and lignans from medicinal herbs and dietary
plants. [246]. Coumarins and their derivatives show
other biological properties such as antibacte-
rial, antiviral, antimalarial, antioxidant, and
furocoumarins, isofurocoumarins, pyranocoumar- antimutagenic activities, inducing cell differ-
ins, bicoumarins, dihydro-isocoumarins, etc. For entiation, and inhibiting xanthine oxidase
example, aesculin, escopoletin, esculetin, scopole- [236,267,268] (Table 19.5).
tin, psoralen isopsoralen, seselin, praeuptorin A,
xanthoxyetin, xanthyletin, bergenin, and wedelo-
lactone are present. Coumarins are major natural
elements in food sources such as vegetables,
19.7.7 Lignans in anticancer activity
fruits, olive oil, and beverages (including tea, cof- Lignans are considered as phenolic acid com-
fee, and wine). For instance, seselin, khellactone, pounds. These are derived from cis-o-hydroxy-
and praeuptorin have been found and isolated cinnamic acid and are dimers resulting from
from Seseli indicum, Ammi visnaga and Peucedanum tail-tail linkage of two coniferl or sinapyl alcohol
praeruptorum respectively [203,266]. Coumarins units [202] (Fig. 19.6). Lignans are found exten-
have been found in several medicinal herbs such sively in plants and are free form as glycosides
as Rutaceae, Magnoliaceae, Umbelliferae, [203]. Lignans mainly consist of lignanolides
Convolvulaceae, Asteraceae, Ranunculaceae, and extracted from Arctium lappa (e.g., arctiin, arcti-
Leguminosae. Coumarins have been found and genin, and matairesional), cyclolignanolides
isolated from A. annua, Angelica sinensis, Citrus extracted from Polygala tenuifolia (e.g., chinensin),
aurantium and Agrimonia Pilosa, including simple bisepoxylignans extracted from Forsythia suspense
coumarins, furanocoumarins(5-hydroxyfurano- (e.g., forsythin and forsythigenol), neolignans
coumarin), pyranocoumarins, and isocoumarins extracted from Magnolia officinalis and Cedrus deo-
respectively [201]. Especially in India, coumarins dara (e.g., magnolol), and other lignans extracted
have been identified in various medicinal herbs, from Schisandra chinensis (e.g., schizatherins, schi-
including Carum Copticum, Foeniculum vulgare, zandrins and wulignan), furofuran lignans from

Cuscuta chinensis, and pinoresinol from Pulsatilla 19.7.8 Quinones as anticancer activity
chinensis [201,206]. The famous antitumor drug
(podophyllotoxin) has been identified and iso- Quinones are present in medicinal herbs and
lated from Podophyllum peltatum, Podophyllum dietary plants; they consist of four types: benzo-
emodi var. chinense [269], which Native quinones, naphthoquinones, anthraquinones, and
Americans used for the treatment of warts [269]. phenanthraquinones [201] (Fig. 19.7). Among nat-
Various lignans, including isoyatein, yatein, ural anthraquinones are major classes of quinones
cubebin, and hinokinin, were found in the that are more broadly distributed in medicinal
Indonesian medicinal plant Piper cubeba L. [270]. herbs and food sources than other natural qui-
In the Netherlands, some lignans (secoisolaricire- nones [202]. Hydroxyanthraquinones possess 13
sinol, matairesinol, lariciresinol, and pinoresinol) hydroxyl groups on the anthraquinone structure.
are consumed daily [271]. Secoisolariciresinol is Quinones are well-distributed in Labiatae,
mainly extracted from seeds of Linum usitatissi- Polygalaceae, Myrsinaceae, Boraginaceae and
mum, and pinoresinol and lariciresinol are Rubiaceae [201,206]. For instance, emblin, embeli-
extracted from the seeds of Sesamum indicum and nol, embeliaribyl ester, and embeliol (benzoqui-
Brassica vegetables. Flaxseeds, sesame seeds, and nones), shikonin, alkannan, acetylshikonin, and
brassica vegetables possess high levels of lignans. juglone (naphthoquinones) were found and iso-
Sesamol, sesamin, and its glycosides are obtained lated from Embelia ribes and Lithosperum
from sesame oil and sunflower oil [203]. erythrorhizon and Juglans regia respectively.
Lignans show significant antioxidant and Phenathraquinones, including tanshinone I, IIA,
anticancer activities due to hydroxyl groups and IIB, were identified and extracted from Salvia
present in the lignan molecules, but several lig- miltiorrhiza. Antharaquinones and its glycosides
nans do not show radical scavenging activity were identified and extracted mainly from roots
[202,243,272]. Lignans have other biological and rhizomes. For example, alizarin, chrysopha-
properties such as antibacterial, antiallodynic, nol, rhein, aloe-emodin, munjistin, physcion, pur-
antiinflammatory, antiviral, antiangiogenesis, purin, pseudopurpurin, emodin-glycoside, and
and antimutagenic properties; they modulate emodin-malonyl-glucoside were extracted from
expression of enzymes, modify signal trans- roots and rhizomes from Pediomelum cuspidatum,
duction pathways and hormone metabolism, P. multiflorum and Rubia cordifolia are found in the
increase detoxification, induce apoptosis by species of Polygalaceae and Rubiaceae
cell cycle blocking, and decrease breast cancer respectively [201,206,273]. Further, a few
cell adhesion [231,234,236] (Table 19.5). For
instance, sesamin could be used for the treat- OH O OH OH O OH OH O OH OH O OH OH O OH
ment of leukemia, breast, skin, and stomach OH O

O O OH O OH O O
cancers; it also exhibits antioxidant properties, chrysophanol emodin aloe-emodin rhein physcion
blocks the cell cycle, and promotes antiinflam- O O OH O OH OH O OH OH O

O CH3
matory effects and induction of apoptosis OH
[203]. Podophyllotoxin has been used for can- OH O

HO
O
C11H29
OH O OH O OH O
cer treatment, including inhibition of DNA juglone embelin alkannan shikonin acetylshikonin
topoisomerase II (topo II). During DNA repli- O

O
O
O
O
O
cation, it reduces torsion tension and condensa- O O O
tion of chromosomes in the nucleus during cell OH
division [269]. Further, matairesinol, pinoresi- tanshinone I tanshinone IIA tanshinone IIB
nol, sescoisolariciresinol, and lariciresinol lig- FIGURE 19.7 The chemical structures of common qui-
nans are essential phytoestrogens [215]. nones from medicinal herbs and dietary plants.

naphthoquinones were identified and isolated (Hvdrastis Canadensis L), Berberidaceae and
from the roots of Zea mays L [274]. Menispermaceae. Quinolone alkaloids like evodia-
Quinones and its derivatives show potential mine was found and isolated from the dried or
antioxidants. Among quinones, hydroxyquinones nearly ripe fruits of Evodia rutaecarpa (Chinese
possess strong antioxidant activity due to dihy- herb). The matrine type of alkaloid are belongs to
droxy groups at the ortho position. hydroxyqui- quinolizidine alkaloids. These alkaloids and its
nones (ortho-dihydroxy substances), including derivatives are naturally obtained from Sophora
purpurin, pseudopurpurin, and alizarin were plants such as Sophora flavescens Ait [278]. Piperine
highly effective, and others were less effective due is one type of piperidine alkaloid, obtained from
to absence of dihydroxyl groups at the ortho posi- Piper longum and piper nigrum, sanguinarine (ben-
tion, including emodin, rhein, chrysophanol, rhein, zopheanthridine) alkaloid, identified and isolated
and aloe-emondin [202]. This indicates the ortho- from the Sanguinaria canadensis L. and Chelidonium
dihydroxy structure in quinone and its derivatives majus L. Schischkinin and montamine belong to
plays an important role in enhancing the radical the indole alkaloids, obtained from Asteraceae
scavenging activity, like the catechol structure in species, such as Centaurea schischkinii (from seeds)
other phenolic molecules. Hydroxyanthraquinones and Centaurea montana (from seeds). Vinca alka-
exhibit remarkably diminished free radical scav- loids are naturally plant-derived anticancer agents
enging activity [275]. Quinones play key functions such as vinblastine and vincristine, which are
in plant metabolites, including redox signaling, commonly occurring bioactive compounds from
pathogen protection, and oxidative phosphoryla- Apocynaceae species. Vinblastine and vincristine
tion. Quinones could block DNA binding, influ- are mainly isolated from C. roseus G. Don and
ence pRb-preventable G2/M cell cycle blocking, other alkaloids are extracted from Toddalia asiatica
and regulate the function of kinases, including L., C. majus L., Fagara zanthoxyloides Lam.,
inhibit casein kinase-2, urease, and stop signal Zanthoxylum nitidum DC., Solanum tuberosum and
transduction pathways [235,237,269,276]. Hence Sophora alopecuroides L., chelerythrine, chelidonine,
quinones and their analogs play important roles in nitidine chloride, solanine, and sophocarpine
cancer prevention. respectively.
Alkaloids are naturally derived plant HBs. As
per the literature, some alkaloids exhibit signifi-
cant anticancer activity, like berberine, evodia-
19.7.9 Alkaloids as anticancer agents mine, matrine, piperine, sanguinarine, and
Alkaloids are the most diverse group of HBs, tetrandrine (Fig. 19.8). But a few alkaloids, includ-
with a heterocyclic ring structure. Most com- ing nitidine chloride, chelidonine, chelerythrine,
monly, a nitrogen atom would be located within lycorine, solanine, and fagaronine, have not had a
the heterocyclic ring structure [277]. Alkaloids are methodical investigation of anticancer properties.
broadly classified based on the chemical structure. Berberine potentially exhibits both in vitro and
Alkaloids include quinolones, isoquinolines, in vivo antitumor activity. It could be found to
indole, piperidine, pyrrolidiens, pyrrolizidines, have efficacy against breast, lung, liver, osteosar-
pyridines, terpenoids, and steroids. Alkaloids are coma, and prostate cancer [279,280]. In addition,
naturally obtained from plants. Isoquinoline alka- berberine shows a wide range of biological prop-
loids like Berberine, terandrine, and berbamine erties, including antibacterial, antiulcer, antiin-
(bisbenzylisoquinoline) alkolides are broadly dis- flammatory, antidiabetes, sedation, development
tributed in Chinese herbs like Rhizoma copidis and of blood vessels, hepatoprotective, and neuropro-
roots of Stephania tetrandra and also identified tective effects [281285]; it could also be used for
from plant species such as Ranuncufaceae the treatment of arrhythmia, diarrhea, diabetes

O
O N
O
O
O
O [291295]. Evodiamine has been less toxic to nor-
N
N N
O N
N H N
mal human cell (blood mononuclear cells) when
N O H
O
O
OH O
OH O
compared with other anticancer agents [293,296].
berberine camptothecin
chelerythrine
9-methoxycamptothecin evodiamine Evodiamine inhibits human breast cancer
O
O
NCI/ADR-Res cells [297]. It also inhibits several
H H O
H
N N
O
N O O enzymes like berberine alkaloid. Evodiamine alka-
N O O
O
H
O
O
O
N
Cl-
loid has been used for the treatment of amenor-
matrine piperine sanguinarine nitidin chloride rhea, postpartum hemorrhage, headache, and
OO
O gastrointestinal disorders. Quinolizidine alkaloids,
O
N
O N
O
O
O
H
N like matrine exhibit a broad range of biological
H H O
O
H
N O
H O
N H properties, including anticancer, antibacterial,
O HO
O
OH O
OH antiasthmatic, diuretic, antiobesity, antirrhythmic,
tetrandrine
O
chelidonine chelerythrine lycorine nephroprotective, cardioprotective, choleretic, and
O
O
O O HO O
hepatoprotective effects [285,298]. Matrine has
OH
O H
O been used for the treatment of different cancer
O N N
O
N
N
O
O
O
cell lines in China. Matrine, like evodiamine, does
fagaronine
O
antofine
O
tylophorine corynoline
not have significant effects on normal cells [299].
Sanguinarine induces blocking the cell cycle at
FIGURE 19.8 The chemical structures of common alko- different phases of a variety of cancer cell lines,
loids from medicinal herbs and dietary plants.
including breast cancer cells, to TNF-related apo-
ptosis inducing ligand-mediated apoptosis [300]
neurasthemia, and so forth [285]. As per the litera- and also exhibits enzyme inhibition. Sanguinarine
ture, berberine has significant anticancer activity could be used for prostate cancer prevention
by interfering with the several aspects of tumor [301]. This alkaloid directly reacts with glutathi-
progression in both in vitro and in vivo investiga- one, resulting in severely depleted cellular GSH
tions. Berberine inhibits the reproduction of sev- and inducing reactive oxygen species (ROS) gen-
eral cancer cell lines in the cell cycle, blocking at eration [302]. Schischkinnin and montamine show
G/M phases and by apoptosis [286288]. potential anticancer effects on colon cancer cells
Although differentiated from clinically deter- [303]. Vinca alkaloids are potential anticancer
mined anticancer agents, the cytotoxic strength is agents for the treatment of breast cancer, lung
very much lower, with an IC50 generally at 10 to cancer, leukemia, testicular cancer, and lympho-
100 μM, depending on the type of cell and dura- mas with a combination of other chemotherapeu-
tion of the treatment [286]. Berberine could inter- tic drugs. Vinca alkaloids are semisynthetic
act with nucleic acids to form berberine-DNA and derivatives obtained from the active substances.
berberine-RNA complexes, respectively [289,290]. As per the literature, other alkaloids such as lycor-
Isoquinoline (berberine) alkaloids could inhibit ine, trigonelline, nitidine chloride, sophocarpine,
several enzymes such as telomerase, and solanine compounds exhibit limited effects
N-acetyltransferease (NAT), and cyclooxygenase- on cancer and its mechanisms.
2 (COX-2) [286]. Evodiamine (quinolone) alkaloid
possesses significant biological properties, such as
anticancer, antiinflammatory, antiobese, antialler-
gic, antianxiety effects. It exhibits both in vivo and 19.7.10 Others as anticancer agents
in vitro anticancer activities, including cell cycle Aromatic volatile oils, including phenolic ter-
blocking, inhibiting angiogenesis, and invasion penoids, phenolic alkaloids, phenolic glycosides,
and metastasis in different cancer cell lines and meta-benzo-triphenol analogs consisting of

one or more aromatic rings attached to one or suffruticosa, A. pilosa and Matteuccia struthiopteris
more hydroxyl groups (Fig. 19.9), are broadly respectively [201,205207]. Oleuropein and trip-
distributed in medicinal herbs and dietary plants tophenlolide has been extracted from olive oil
(food source). Phenolic alkaloids were identified and T. wilfordii [201,205].
and determined in Chinese traditional medicinal Supplemental phenolic substances show a
plants. Magnoflorine alkaloid was identified in broad range of biological properties
Coptis chinensis, Phellodendron amurense, T. asiatica, (Table 19.5). For instance, magnoflorine pos-
and medicinal herbal tea in Okinawa [304]. sesses antihuman immunodefiency virus (HIV)
Nitidine, dihydronitidine, and phellodendrine activity; triptophenlolide exhibits comprehensi-
was found in Z. nitidum and P.amurense [201]. ble inhibitory effects on lymphocytes and oxi-
Volatile oils and aromatic terpenoids are found dative free radical cyclization reactions
in Indian and Chinese medicinal herbs and die- (especially Mn(III) reactions); oleuropein and
tary plants. Carnosic acid was found in sage, carnosol have cell cycle blocking and antiin-
sweet basil, Andrographis paniculata, Xanthium flammatory effects, antioxidant activity and
sibiricum and Nerium oleander; rosemary consists induction of apoptosis; anethole and carnosol
of carnosol and epirosmanol; mint possesses potentially suppress AP-I activation; eugenol
menthol; thyme possesses thymol; oregano con- possesses significant antiproliferation activity
tains carvacrol; star anise possesses anethole; at various stages of progression, arresting cells
clove has eugenol; Zanthoxylum americanum in the S phase of progression, inhibiting mela-
(Pricklyash) possesses estragole and xanthoxylin; noma cells; and significantly, antibacterial,
cinnamon has cinnamaldehyde and triptopheno- antiviral, antiseptic and analgesic agents were
lide from Tripterygium wilfordii [201,205,206]. used as traditional medicine in Asia
Moreover, normal phenols (only C6 skeleton) [213,304306]. Natural phenolic substances
were identified from aromatic medicinal plants. could reduce the formation of carcinogenic
For example, P-cresol and vanillin were identi- acrylamide and heterocyclic amines [307].
fied from A. sinensis [201]. Syringaresinol, paeo- Many carbohydrate foods, including potatoes
nol, m-benzo-triphenols, filicic acids are and cereals (after baking) possess high amount
extracted from Clematis chinensis, Paeonia of acrylamide [308]. The International Agency
for Research on Cancer (IARC) considers acryl-
amide as highly carcinogenic for humans [307].
O HO
O Moreover, heterocyclic amines are identified
OH OH
O O
HO
N
HO
O
HO
O
HO O
and isolated from pyrolysis products of amino
HO
O O O O acids and proteins, thermally processed cooked
OH OH
O
magnoflorine carnosol epirosmanol HO

O
meat and fish. Acrylamide is highly genotoxic
OH
OH and carcinogenic to test animals [307].
oleuropein
O
O
O
O Acrylamide could form DNA adducts to
O
O O HO
O
O OH
induce DNA damage. [308]. Some plants,
N OH
O O
O
O
O O including thermally processed plant extracts
dihydronitidine syringaresinol triptophenolide pacenol
like grape seeds, bamboo leaves, tea, and
O
O
OH
O OH
OH
O
OH
gingko, could reduce acrylamide [309].
OH
OH OH OH Moreover, dietary plant (food sources) extracts
O
from cherry, blackberry, and grapes (fruits),
vanillin p-cresol
anchole
eugenol estragole carvacrol thymol
garlic, rosemary, sage, thyme and marjoram
FIGURE 19.9 The chemical structure of some other (spices), pine bark, soy, and tea could show
substances from medicinal herbs and dietary plants. potential antioxidant effects, reduction of

acrylamide, decreasing potential mutagenic given in (Fig. 19.10). The mushroom cell wall
and carcinogenic harm of certain cooked foods possesses high molecular weight materials that
[308,309]. are not digested and absorbed in the human
Other than medicinal plants, several fungi intestine but could absorb carcinogenic materials
have been identified with successful anticancer like chitin, metals, and free radicals. This way,
agents on different cancer cell lines. A few fungi these high molecular weight substances could
could pass preclinical investigations to become be used as anticancer agents against different
essential candidates for further clinical testing. type of cancers [313]. Mushroom proteins
For instance, Gonodeerma lucidum, a saprophytic include ribonucleases, lectins, hemolysins, nebro-
fungus frequently grows in a humid ventilated deolysin, calcaelin, and bolesatine, which are
condition with a high temperature. As per used for treatment of different cancers, such as
modern classification, it is classified as lung and breast cancers [314,315]. These proteins
Ganodermoideae (Basidiomycotina). This fungus are extracted from Amanita phalloides, C. caelata,
has long been used as traditional medicine. The Ganoderma carpense, Polyporus adusta, Pleurotus
chemical constituents were extracted, identified, ostreatus, Pleurotus nebrodensis and Pleurotus erygii
and found to include enzymatic proteins, glyco- [314,315]. Generally, mushrooms are a rich
proteins, polysaccharides, and other active chem- source of vitamin D, because they are exposed to
ical constituents such as fatty acids, steroids, and ultraviolet B light. Light-exposed mushrooms
terpenoids [310]. G. lucidum fungus shows vari- could be used for the treatment of a variety of
ety of biological properties, including strong anti- cancers, including colon, breast, pancreatic, and
cancer and antioxidant activity [311]. The ovarian cancer by choosing variety of enzymes,
anticancer activity of this fungus could function proteins, and signaling pathways [316318].
through various mechanisms like cell death
through apoptosis, blocking the cell cycle at the
G2/M phase in cancer cells, inhibition of
HCT117 cell moderated by the inhibition of
nuclear translocation of NF-KB, and degradation
of IKB-α inhibitor [312]. Mushrooms are also
used as traditional medicine for the treatment of
cancer. For example, Coriolus versicolor and
Lentinus edodes are widely cultivated in Japan
and China. The major chemical constituents of C.
versicolor and L. edodes mushrooms consist of
polysaccharides, especially β-D glucans, polysac-
charide peptide, and protein-bound polysacchar-
ides. Polysaccharides found in the fruiting
bodies and mycelial mass of Macromycetes
show numerous biological properties. The poly-
saccharides, include glucans and tegafur; glucans
could be used in the treatment of breast, lung,
head, neck, and gastric cancers, increase cellular
immunity in the cancer cell, prevent invasion
and metastasis, induce gene expression of cyto- FIGURE 19.10 Mechanism of anticancer activity of
kines, and act as macrophage activator. wild mushrooms, T-helper, major histocompatibility com-
Mushroom polysaccharides and their targets are plex, Cluster of differentiation 8 and Natural killer cells .

19.9 Conclusion and future prospects 461
19.8 Various schemes for the

development of anticancer herbal
biomolecules
The promise of medicinal herbs and dietary

plants as therapeutic agents mainly depends
upon the quality and quantity of the active
HBs in them. These active HBs are different
from species to species, season, longitude, lati-
tude, altitude, climate, and age. Therapeutic
functions and their levels are different with dif-
ferent plant parts. These active HBs could be
used as anticancer agents; however, further
research is needed. The isolation and purifica-
tion of bioactive HBs’ chemical constituents FIGURE 19.11 Comprehensive scheme of anticancer
might involve different approaches, including herbal biomolecules synthesis, improvement, characteriza-
isolation assays, bioassay-guided fractionation, tion and prospective use as cancer therapeutic agent.
and combinatorial chemistry. Using analytical
methods, these bioassay-guided fractionations dose concentration etc. should be explored for
could be used to isolate different bioactive HBs further drug designing. The detailed scheme of
compounds from mixtures of the substances. bioactive compound synthesis optimization,
The procedures start with the natural crude characterization, testing, and potential applica-
extracts test (from wet or dry plant material) tions as cancer therapeutic agents is shown in
with confirmed biological properties. Then, Fig. 19.11.
suitable procedures could be used for the frac-
tionations of bioactive extracts, and bioactivity
could be tested using different analytical meth-
ods, like high performance liquid chromatogra- 19.9 Conclusion and future prospects
phy (HPLC), thin layer chromatography (TLC),
Fourier transformation of infrared spectros- HBs, such as phenols, flavonoids, tannins,
copy (FT-IR), nuclear magnetic spectroscopy quinones, lignins, alkaloids, etc., are major con-
(NMR) and mass spectroscopy, etc. For separa- stituents of medicinal herbs and dietary plants
tion of bioactive fractions, suitable mobile (food sources), including fruits, spices, cereals,
phases (high polarity to nonpolarity) and sta- vegetables, and beverages. HBs and their ana-
tionary (polar or nonpolar) phases could be logs exhibit a wide range of valuable biological
used. These procedures should change the properties, which contribute in vivo and
purity, quality, and quantity of the bioactive in vitro antioxidant and anticancer properties.
HB compounds. After isolation and purifica- HBs could have a massive clinical impact on
tions of these HBs, they should be investigated cancer prevention. The increasing frequency of
for in vitro or in vivo anticancer properties. If cancer, along with diverse limitations in tradi-
HBs exhibit anticancer properties, then other tional therapy such as the high cost and high
aspects, such as pharmacokinetics, pharmaco- toxicity of current anticancer drugs, has created
dynamics, immunogenicity, metabolic fate, bio- an acute challenge for researchers to develop
safety, and side effects, drug interactions, and and design an alternative and ecofriendly,

cost-effective, and biodegradable approach in a potentials and mechanisms. Front Pharmacol

greener way. In the current framework, HBs 2019;10:119.
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C H A P T E R

19.1 Introduction worldwide [4], and the mortality rate in 2018

Herbal Biomolecules in Healthcare Applications

TABLE 19.1 Different forms of top most organ based

Prostate 36,50,030 50,17,810

Herbal Biomolecules in Healthcare Applications

Herbal Biomolecules in Healthcare Applications

Herbal Biomolecules in Healthcare Applications

Artemisia annua Artemisinin Liver, breast, and pancreatic cancer [36]

Matricaria chamomilla Apigenin Colorectal cancer [41]

Colchicum autumnale Colchicine Hodgkin’s lymphoma, chronic granulocytic leukemia [50]

Passiflora caerulea Chrysin Colorectal cancer [53]

Withania somnifera 5-Fluorouracil Human cervical cancer cell [59]

Herbal Biomolecules in Healthcare Applications

TABLE 19.2 (Continued)

T. baccata Larotaxel Breast, bladder, and pancreatic cancer [67]

Moringa oliefera Niazinine A Blood cancer [72]

Zingiber officinale 6-Shogaol Ovary cancer [89]

Herbal Biomolecules in Healthcare Applications

Catharanthus roseus Vincristine Lymphocytic leukemia [42]

Herbal Biomolecules in Healthcare Applications

Herbal Biomolecules in Healthcare Applications

TABLE 19.3 Natural products (primary metabolites) anticancer activity.

Abrus recatorius Fabaceae Abrin Colon cancer [110,111]

Allium spp. Alliaceae Dimethyl disulfide Colon cancer cell [123,124]

Brassica spp. Brassicaceae Sulforaphane Human prostate cancer cells [136,137]

Herbal Biomolecules in Healthcare Applications

19.7.1 Phenols as anticancer activity lignans, neolignans ((C6-C3)2 skeleton; ex:

Herbal Biomolecules in Healthcare Applications

Aesculetin Aesculus hippocastanum Cervical [139]

Baicalein S. baicalensis Prostate, gastric [146]

Cuphiin D1 Cuphea hyssopifolia Leukemia, epidermoid, hepatocellular, [156]

Caffeic acid Cinnamomum verum Colon er [157]

Epigallocatechin-3-gallate C. sinensis Leukemia, hepatoma, melanoma, breast, lung [164166]

Hesperetin Citrus spp. Breast [177]

Herbal Biomolecules in Healthcare Applications

TABLE 19.4 (Continued)

Kaempferol Kaempferia galangal Hepato, pancreatic, osteosarcoma [179181]

Phloretin Malus spp. Melanoma, hepatoma [189]

Sinapic acid Brassica spp. Colon, cervical [191]

7-Hydroxycoumarin Hieracium pilosella Lung [197]

(2)-Syringaresinol Castela emoryi Leukemia [199]

Herbal Biomolecules in Healthcare Applications

Hydroxybenzoic acid Protocatechuic acid Gallic acid

Salvianolic acid Chlorogenic acid Cynarin1,3-dicaffeoylquinic acid

Herbal Biomolecules in Healthcare Applications

Herbal Biomolecules in Healthcare Applications

Inhibition of cell HXT, baicalein, apigenin, Inhibit expression of cell- [203,221,222,240,241]

Herbal Biomolecules in Healthcare Applications

TABLE 19.5 (Continued)

Apigenin, chebulinic acid, and

Regulation of Gossypol, isoflavones: Some are important [204,214,231,244]

Herbal Biomolecules in Healthcare Applications

phenol and its analogs, flavonoids also gener-

Herbal Biomolecules in Healthcare Applications

Herbal Biomolecules in Healthcare Applications

such as ortho-dihydroxyl or galloyl groups. trans-resveratrol

High molecular weight tannins possess high O