Phytochem Rev
DOI 10.1007/s11101-014-9366-0
Compounds from Allium species with cytotoxic
and antimicrobial activity
Virginia Lanzotti • Felice Scala •
Giuliano Bonanomi
Received: 6 February 2014 / Accepted: 27 May 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract Garlic (Allium sativum L.) is a bulb-
shaped plant belonging to the Allium genus which
also includes onions (Allium cepa L.), leek (Allium
ampeloprasum L. var. porrum Gay), shallot (Allium
ascalonicum L), scallion (A. fistulosum L.) and chives
(Allium schoenoprasum L.). The biological activity of
garlic has been known since ancient times. Babylo-
nians, Egyptians, Phoenicians, Greeks and Romans
used garlic as a remedy for intestinal disorders,
respiratory infections, skin diseases, bacterial infec-
tions, worms, wounds and tumors. In particular, before
the discovery of antibiotics, garlic has been used
against amoebic dysentery and epidemic diseases such
as typhus, cholera, diphtheria, and tuberculosis. To
date, more than 3,000 publications scientifically
supported the use of garlic in the ethno-medicine.
But what makes garlic and Allium species effective
against cancer? The effect of garlic may arise from its
antibacterial properties or from its ability to block
formation on cancer-causing substances, half the
activation of cancer causing substances, enhance
DNA repair, reduce cell proliferation or induce cell
death. Epidemiological studies have found that an
increase of consumptions of Allium spp. reduce the
risk of prostate and gastric cancers and this has been
V. Lanzotti (&)  F. Scala  G. Bonanomi
Dipartimento di Agraria, Università di Napoli ‘‘Federico
II’’, Via Università 100, 80055 Portici, Napoli, Italy
e-mail: lanzotti@unina.it
mainly related to two main classes of compounds: the
apolar sulphur compounds and the polar saponins.
These latter compounds, compared to the more studied
thiosulphinates, have the advantages of not being
pungent and more stable during cooking. Recently,
there has been increasing scientific attention given to
such compounds. In this paper, the literature about the
major volatile and non-volatile organic compounds of
garlic and other Allium plants has been reviewed.
Particular attention is given to the compounds pos-
sessing antibacterial and cytotoxic activity in garlic
and in the other Allium species and their mechanism of
action.
Keywords Garlic  Onion  Anticancer activity 
Antioxidant activity  Antibacterial activity
Introduction
Garlic and the other Allium species, such as onions,
leek, shallot, scallion and chives, have been known
since ancient times for their health benefits. Babylo-
nians, Egyptians, Phoenicians, Greeks and Romans
used garlic as a remedy for intestinal disorders,
respiratory infections, skin diseases, bacterial infec-
tions, worms, wounds and tumors (Block 1985). In
particular, before the discovery of antibiotics, garlic
has been used against amoebic dysentery and epi-
demic diseases such as typhus, cholera, diphtheria, and
123

tuberculosis. It is documented that garlic was largely
used during the World War II to treat wounds of
soldiers and applied directly to wounds to inhibit the
spread of infection. To date, more than 3,000
publications, one thousand published in the past
decade, scientifically supported the use of garlic in
the ethno-medicine. Several population studies have
shown an association between increased intake of
garlic and reduced risk of cancers of gastro-intestinal
tract. The effect of garlic may arise from its
antibacterial properties (Ruddock et al. 2005) or
from its ability to block formation on cancer-causing
substances (Shenoy and Choughuley 1992), half the
activation of cancer causing substances (Miner
2001), enhance DNA repair (L’vora and Zasukhina
2002), reduce cell proliferation or induce cell death
(Hsing et al. 2002).
Epidemiological studies have found that an
increase of consumptions of Allium spp. reduces the
risk of prostate and gastric cancers and this has been
mainly related to two main classes of compounds: the
apolar sulphur compounds and the polar saponins. In
this paper, the literature about the major volatile and
non-volatile organic compounds of garlic and other
Allium plants has been reviewed. Particular attention is
given to the compounds possessing cytotoxic activity
in garlic and in the other Allium species and their
mechanism of action.
Fig. 1 Organic sulphur compounds from Allium. Abbrevia-
tions used: dially sulphide (DAS), diallyl disulphide (DADS),
diallyl trisulphide (DATS), diallyl tetrasulphide (DATTS),
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Phytochem Rev
Sulphur compounds in fresh and processed bulbs:
allicin, ajoenes, dialkenyl and dialkyl sulphides,
S-allylcysteine (SAC) and S-allylmercaptocysteine
(SAMC)
The chemistry of garlic is complex and it has been
shown to develop a self-protective mechanism against
microorganisms and other pathogens. The main
responsible of this mechanism are sulphur compounds
that give to garlic its characteristic smell. The first
sulphur-compound discovered from garlic was allicin
(diallyl thiosulphinate) (1, Fig. 1), reported by Cav-
allito and Bailey (1944). It is an odorous and
extremely unstable metabolite not present in garlic
bulbs. Its primary precursor in intact bulbs is glutamyl
L-cysteine that is hydrolysed and oxidized to allin
(S-allylcysteine sulphoxide) (Fig. 2). It accumulates in
bulbs during their storage and cool temperature. When
the bulbs are cutted or crushed alliin is transformed
into the alkenyl alkene thiosulphinate allicin by the
enzyme alliinase (Fig. 2). Allicin and the other
thiosulphinates immediately decompose to sulphide
compounds, including ajoenes, diallyl sulphide
(DAS), diallyl disulphide (DADS), diallyl trisulphide
(DATS), dipropyl disulphide (DPDS) (2–8, Fig. 1). In
addition to these metabolites the bulbs also contain
small amounts of SAC and SAMC (9–10, Fig. 1)
formed by c-glutamyl L-cysteine catabolism (Fig. 2).
dipropyl disulphide (DPDS), S-allylcysteine (SAC), S-allylmer-
captocysteine (SAMC)
Phytochem Rev
Fig. 2 Chemical changes in
organic sulphur compounds
in garlic bulbs containing
high amounts of c-glutamyl
L-cysteine. This compound
is the precursor of alliin that
is also present in the bulbs.
After cutting the bulbs the
enzyme alliinase rapidly
convert alliin into allicin
that in turn gives rise to the
other organic sulphur
compounds. c-glutamyl
L-cysteine is converted
without passing through
alliin and allicin to SAC
When the garlic is processed the compounds present in
plants rapidly are transformed into hundreds of sulphur
compounds. In particular, allicin once formed is converted
into other thiosulphinates and for this reason is not present
in intact garlic or in garlic products. At the same time
allicin has been discovered, the use of antibiotics to treat
infections was just reported. Thus, allicin was patented for
its antibiotic and antifungal effects as antimicrobial agent
in vitro. Later on, it has been shown that is not the active
compound in vivo because the acidity of the stomach
prevents the formation of allicin (Freeman and Kodera
1995). In fact, no allicin was detected in human blood after
ingestion of Allium or allicin-based products.
Processed garlic and digested garlic contain other
sulphur compounds that are also less odorous, water
soluble and show interesting biological properties.
Among these, DATS has been reported to induce
apoptosis of the postharvest pathogen Penicillium
expansum on citrus (Liu et al. 2009). In addition, SAC
and SAMC, present in many garlic preparation at
different concentrations (Lawson 1993), have shown the
ability to reduce carcinogen bioactivity (Lee et al. 1994).
It has to be considered that processed garlic contains
sulphur-compounds different from those found in intact
cloves of garlic and that these compounds vary
depending from the manufacturing processing.
Sulphur compounds in garlic products
The essential oil of garlic is obtained by steam
distillation of cloves and contain a variety of
sulphides, mainly DADS and DATS (Block 1985).
The garlic cloves are heat-distilled or extracted with
apolar organic solvents such as hexane thus eliminat-
ing the water-soluble organic compounds. Allicin is
not present in the oil. Commercially garlic oils are
based on vegetable oil with addition of small amounts
of garlic oil because of its pungency.
Garlic powder is obtained from garlic cloves after
crushing, drying and pulverization. This is considered
the better garlic product containing the same bioactive
compounds of fresh garlic. However, Iberl et al. (1990)
showed that garlic constituents are present in different
concentrations. In fact, while the main sulphur com-
pound is alliin in both materials, its concentration vary
from 0.8 % in fresh cloves to 1 % in dried powder. A
dehydration process without loss of ingredients would
result in a concentration of alliin around 2–2.5 %. The
obtained value in garlic powder of 1 % indicates that
more than half of alliin is lost during dehydration.
Allicin is present in garlic powder in undetectable
amounts (\ 1 ppm). However, some garlic powder
products indicate an allicin-potential that in any case
only reach the 5 % of the weight in stimulated gastric
fluid compared with water (Freeman and Kodera 1995).
This is due to the inactivation of alliinase at acidic pH of
the stomach (pH B 3) indicating that allicin is not the
active compound in vivo.
Garlic oil macerate is prepared by infusion of fresh
garlic into oil. During this process alliin is transformed
into allicin that rapidly decompose to ajoene and
sulphides (Block 1985). There are no adequate study
on the standardization of such products.
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Garlic extract is prepared by extracting cloves of
garlic with hydroalcoholic solutions. The organic
extract is concentrated or lyophilized thus obtaining a
powder rich in water-soluble organic compounds,
including sulphur compounds, saponins and flavo-
noids. Among the sulphur compounds, SAC and
SACM are the major constituents present. The extracts
are aged up to 20 months giving rise to aged garlic
extract (AGE). During this time the content of volatile
sulphur compounds decreases because they are con-
verted into stable sulphur compounds, such as SAC
and SAMC. For this reason, AGE is considered a safe
and healthy product.
Antimicrobial activity of sulphur compounds
Allicin (1, Fig. 1) is a potent antimicrobial compound.
It is able to inhibit at low concentrations, with an LD50
often within the range of 3–20 lg ml-1, many fungi,
gram-positive and gram-negative bacteria, pathogenic
protozoa and also viruses (Table 1). Antifungal activ-
ity of allicin was clearly demonstrated by Yamada and
Azuma (1977) against several important genera of
human pathogens including Candida, Cryptococcus,
Trichophyton, Epidermophyton and Microsporum.
Allicin can act synergistically with synthetic fungi-
cides. An early study found that streptomycin and
chloramphenicol synergize with allicin in inhibiting
Mycobacterium tuberculosis (Gupta and Viswanathan
1955). Jonkers et al. (1999) reported a synergistic
interaction between the antibiotic vancomycin and
allicin in the inhibition of several antibiotic-resistant
enterococci. A similar synergistic interaction was
reported between the cuprous ion, largely used as a
broad-spectrum fungicide, and allicin in the inhibition
of the yeast Saccharomyces cerevisiae (Ogita et al.
2005). The bactericidal activity of allicin has been
reported against at least 25 saprophytic and pathogenic
bacteria such as Bacillus spp., Enterococcus spp.,
Escherichia coli, Helicobacter pylori, Salmonella
typhimurium, Staphylococcus aureus and Vibrio chol-
era (Table 1). Recently, Cutler and Wilson (2004)
reported that allicin was effective against methicillin-
resistant Staphylococcus aureus strains.
Allicin has a low toxicity towards mammalian cell
cultures with negative effects generally observed at
concentrations higher than 60 lg ml-1 (Ankri and
Mirelman 1999). The different responses of microbial
and mammalian cells to allicin is likely related to the
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Phytochem Rev
action mechanisms of this compound. The antimicro-
bial activity of allicin has been associated with the
inhibition of sulfhydryl-dependent enzymes (Wills
1956) such as alcohol dehydrogenase, thioredoxin
reductase, and RNA polymerase. In many cases, the
addition of both cysteine and glutathione reduced the
inhibitory effects of allicin because these two com-
pounds react with allicin disulfide bond, thus prevent-
ing cell damage. Glutathione occurrence in
mammalian cells may explain their limited sensitivity
to allicin compared to microbial cells which do not
contain or have a very small amount of this compound
(Davis 2005).
E- and Z-ajoene exhibited broad-spectrum antimi-
crobial activity against gram-positive and gram-neg-
ative bacteria (Yoshida et al. 1987; Naganawa et al.
1996), fungi (Yoshida et al. 1998; Ledezma et al.
2000) and protozoa (Perez et al. 1994; Millet et al.
2011) (Table 1). Moreover, the few available studies
indicate that ajoene has a more potent antiviral activity
compared to allicin and other Allium derived organo-
sulphur compounds (Weber et al. 1992). As reported
for allicin, the addition of cysteine greatly reduces the
inhibitory effect of ajoene, likely as a result of the
interaction between the amino acid and the disulfide
bonds of the compound (Naganawa et al. 1996).
Antimicrobial activity has been reported for several
allyl sulphide compounds (4–7, Fig. 1) and seems to
be related to the number of disulphide bounds, i.e.
DATTS[DATS[DADS[DAS (Tsao and Yin 2001).
Cytotoxic activity and mechanism of action
of sulphur compounds
Since Weisberger and Pensky (1958) demonstrated,
in vitro and in vivo, that thiosulfinate extracts from
garlic inhibit the tumor cell growth, many studies have
been carried out to elucidate the role and the mech-
anisms of action of these compounds as chemopre-
ventive or anticarcinogen agents. Attention focused
mostly on allicin, the major biologically active
component of fresh garlic. Allicin may exert its
anticarcinogen action in different ways such as the
alteration of carcinogen metabolism (Guyonnet et al.
1999); inhibition of the procarcinogen activation by
affecting the cytochrome P450 (Dion et al. 1997;
Khanum et al. 2004); inhibition of oxidative damage
due to the antioxidant action (Perchellet et al. 1990);
Phytochem Rev

Table 1 List of organic sulphur compounds from the genus Allium with in vitro activities on cancer cells
Cytotoxic Cancer Cell line and References
compounds bioassay

Allicin (1) Cervical carcinoma HeLa Hirsch et al. (2000), Oommen

et al. (2004), Azadi et al. (2009)
Breast cancer MCF-7
Cervical carcinoma SiHa Oommen et al. (2004)
Colorectal adenocarcinoma SW480
Colon carcinoma LoVo Guang et al. (2004)
Colorectal adenocarcinoma Caco-2 Bat-Chen et al. (2010)
Colorectal carcinoma HCT-116
Colorectal adenocarcinoma HT-29 Hirsch et al. (2000), Bat-Chen
et al. (2010)
Endometrial adenocarcinoma Ishikawa
Gastric adenocarcinoma SGC7901 Zhang et al. (2010)
Gastric cancer (check) MGC-803 Ha and Yuan (2004), Lan (2004),
Zhang et al. (2007)
Gastric cancer (check) SGC-7901
Gastric carcinoma AGS Park et al. (2005)
Glioblastoma U87MG Cha et al. (2012)
Leukemia B-CLL PBMC Arditti et al. (2005)
Lymphoma CD20? MCL
Leukemia HL60 Miron et al. (2008)
Leukemia U937
Lymphoma EL-4 Wang et al. (2012a)
Murine lymphoma (check) L5178Y Padilla-Camberos et al. (2010)
– NIH-3T3 Prager-Khoutorsky et al. (2007)
Breast cancer ErbB2? Miron et al. (2003)
E- and Z-Ajoene Melanoma B16/BL6 Taylor et al. (2006)
(2,3)
Colorectal adenocarcinoma HT-29
Lung carcinoma A549
Breast adenocarcinoma MDA-MB231
Pancreatic adenocarcinoma PANC-1
Breast adenocarcinoma SKBR-3
Leukemia HL-60 Dirsch et al. (2002), Li et al.
(2002), Antlsperger et al. (2003),
Terrasson et al. (2007)
Colon adenocarcinoma DLD-1 Dirsch et al. (1998)
Squamous carcinoma A431
Neuroblastoma SH-SY5Y
Melanoma B16F10 Ledezma et al. (2004)
a
Leukemia CD34 Ahmed et al. (2000), Hassan
(2004)
Leukemia CD7

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 Phytochem Rev

Table 1 continued
Cytotoxic Cancer Cell line and References
compounds bioassay

Leukemia Human resistant

myeloid
Neuroblastomab SK-N-AS Terrasson et al. (2007)
– MRC5
Astrocytoma U373MG
Leukemia JURKAT
Breast cancer MCF-7 Li et al. (2002)
Nasopharyngeal carcinoma KB
Hepatocellular carcinoma Bel 7402
Gastric carcinoma BGC 823
Colon carcinoma HCT
Cervical carcinoma HeLa
Basal cell carcinoma TE354T Tilli et al. (2003)
Lymphoma BJA-B Scharfenberg et al. (1990, 1994)
Diallyl sulphide Melanoma A375 Wang et al. (2012b)
(DAS) (4)
Carcinoma (check) BCC
Prostate carcinoma LNCaP Pinto et al. (1997)
Lung carcinoma H460 Hong et al. (2000)
Lung carcinoma NSCLC
Diallyl disulphide Melanoma A375 Wang et al. (2012b)
(DADS) (5)
Carcinoma (check) BCC
Colorectal adenocarcinoma HCT-15 Sundaram and Milner (1996), Park
et al. (2002)
Leukemia HL60 Kwon et al. (2002)
Lung carcinoma H460 Hong et al. (2000)
Lung carcinoma NSCLC
Lung carcinoma A549 Sundaram and Milner (1996)
Melanoma SK MEL-2
Neuroblastoma SH-SY5Y Filomeni et al. (2003)
Prostate carcinoma LNCaP Pinto et al. (1997)
Diallyl trisulphide Melanoma A375 Wang et al. (2012b)
(DATS) (6)
Diallyl tetrasulphide Colorectal carcinoma HCT-116 Saidu et al. (2013)
(DATTS) (7)
S-Allylmercaptocysteine Prostate carcinoma LNCaP Pinto et al. (1997)
(SAMC) (10)
Leukemia HEL Sigounas et al. (1997)
Leukemia OCIM-1
Breast cancer MCF-7
Prostate carcinoma CRL-1740
S-Allylcysteine Prostate carcinoma LNCaP Pinto et al. (1997)
(SAC) (9)
Colorectal adenocarcinoma HCT-15 Sundaram and Milner (1996)

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Phytochem Rev
Table 1 continued
Cytotoxic Cancer
compounds
Lung carcinoma
Melanoma
Dipropyl disulphide Colorectal adenocarcinoma
(DPDS) (8)
Lung carcinoma
Melanoma
a
Ajoene acts in interaction with cytarabine or fludarabine
b
Ajoene reduces the spread of the HCMV virus
inhibition of cellular proliferation by induction of
apoptosis and inhibition of cell division (Perchellet
et al. 1990); prevention of chromosomal damage
(anticlastogenic effect) (Lau et al. 1990; Khanum et al.
2004); and inhibition of the lipoxygenase and cyclo-
oxygenase activities (antiinflammatory effect) (Per-
chellet et al. 1990; Rose et al. 2005).
The action mechanisms of allicin have been studied
in a range of cancer cells including SiHa cells (human
cervical cancer cell line) (Oommen et al. 2004),
HepG2 (hepatocellular carcinoma cell line) (Seger
and Krebs 1995; Lee et al. 2002; Roux and Blenis
2004; Zhang et al. 2007), SGC-7901 (gastric carci-
noma cell line) (Sun and Wang 2003; Hirsch et al.
2000), CF-7 cells (human breast cancer cell line)
(Hirsch et al., 2000) and U87MG human glioma cells
(Cha et al. 2012).
Here we discuss some of the mechanisms reported
for the cytotoxic activity of this sulphur compound.
Allicin induced-apoptosis was one of the most
observed mechanisms. On cancer SGC-7901 cells,
Zhang et al. (2010) found that allicin reduced cell
viability in gastric cancer cells in a dose- and time-
dependent manner, by induction of apoptosis. The
molecular mechanism included processes related to
apoptosis such as cytochrome c release from the
mitochondria and increased caspase-3, -8, and -9
activation. Upregulated expression of bax and fas, two
genes involved in the physiological regulation of
programmed cell death, was also observed. In another
study on the same type of cells, SGC-7901 (Sun and
Wang 2003) apoptosis (arrest in G2/M phase) was
related to decreased telomerase activity. In the pre-
sence of a decline of this enzymatic activity, telomeres
are shortened with each round of cell division until
mitoses of cells are arrested and apoptosis takes place.
Cell line and References
bioassay
A549
SK MEL-2
HCT-15 Sundaram and Milner (1996)
A549
SK MEL-2
Allicin was also compared with 30 azido-30 -deoxythy-
midine (AZT), a reverse transcriptase inhibitor which
is known to induce apoptosis by inhibiting telomerase
activity. Allicin resulted more effective than AZT, but
arrested cells at the G 2/M phase while AZT did it at the
S phase. This indicates that the mechanism of allicin on
telomerase activity inhibition is different from that of
AZT and telomerase activity lacks cell cycle regulation
(Kyo and Inoue 2002; Holt et al. 1996, 1997).
Induction of apoptosis associated with an increase
in caspase-3 activity was also found in L5178Y
lymphoma cells (Padilla-Camberos et al. 2010);
similarly, in SiHa (human cervical cancer), L-929
(murine fibrosarcoma), SW480 (human colon cancer)
and HeLa (human cervical cancer) cell lines, allicin
induced the formation of apoptotic bodies, activation
of caspases-3, -8 and -9 and cleavage of poly(ADP-
ribose) polymerase (Oommen et al. 2004). A very
detailed study on allicin mechanisms was carried out
on U87MG human glioma cells (Cha et al. 2012). As
for gastric cancer cells, allicin activity occurred
through induction of apoptosis. Some representative
mechanisms involved in apoptosis including the
mitochondrial pathway, activation of mitogen-acti-
vated protein kinases (MAPKs), caspase cascade and
oxidant enzyme system were investigated. It was
demonstrated that Bax expression increased, while
Bcl-2 expression decreased. The Bcl-2 family might
be involved in apoptosis through an interaction
between the pro- and anti-apoptotic proteins (Gross
et al. 1999; Coultas and Strasser 2003; Dejean et al.
2005; Youle and Strasser 2008). The down- and up-
regulated expression of Bcl-2 and Bax, respectively,
suggest that allicin-induced apoptosis is related to the
mitochondrial pathway. Moreover, apoptosis in gli-
oma cells was not mediated by the caspase cascade as
123

demonstrated for gastric cancer cells, but by the
MAPK/ERK signaling pathway. This study also
demonstrated the involvement of reactive oxygen
species (ROS) in apoptosis. It is known that ROS may
be associated with apoptosis because they are able to
cause damage to membranes and other cellular
structures (Inoue et al. 2000; Kannan and Jain 2000;
Circu and Aw 2010) and that antioxidant enzymes
protect the cells from oxidative damage. Results
obtained showed that allicin-induced apoptosis in the
U87MG cells was down-regulated by the antioxidant
enzyme system.
Although the biological effects of allicin have been
related to its ability to react with thiol groups (Prager-
Khoutorsky et al. 2007) the precise mechanisms
underlying its cytostatic activity are not clear. Prag-
er-Khoutorsky et al. (2007) demonstrated that cultured
NIH-3T3 mouse fibroblasts treated with allicin
showed some characteristic changes in their shape
and motility, i.e. cells became unable to polarize and
migrate directionally. These effects are similar to
those caused by microtubule-disrupting drugs such as
nocodazole (Vasiliev et al. 1970; Vasiliev 1991).
Allicin caused microtubule depolimerization without
disrupting the actin cytoskeleton, and blocked the
polymerization of pure tubulin. Compounds with
sulfhydryl (SH)-reducing such as 2-mercaptoethanol
and dithiothreitol suppressed the effect of allicin on
microtubule polymerization. This suggests that allicin
inhibits polymerization of tubulin by reacting with its
SH groups.
Saponins
Most of the chemical and biological studies on garlic
and related Allium species have been performed on
sulphur compounds. However, recently the attention
was focused on saponins that are water soluble
compounds and more stable to cooking (Lanzotti
2005, 2006, 2012; Lanzotti et al. 2012a, b, 2013).
Fresh or dried Allium plants are extracted with
MeOH or acetone and the the organic extracts are
resuspended in water and then extracted with butanol
to eliminate in the water phase the salts, sugars and
aminoacids. The butanol extract is purified by con-
secutive purification steps by medium pressure liquid
chromatography (MPLC) and high performance liquid
chromatography (HPLC) in reverse mode and eluting
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Phytochem Rev
with a gradient solvent system from water 100 % to
methanol 100 %. The fractions obtained are analysed
by TLC (SiO2, butanol/acetic acid/water 60:15:25)
and NMR to check their degree of purity. Final
purification is obtained by C-18 reversed-phase HPLC
equipped with semi-preparative and analytical col-
umns (Lanzotti 2006). The approach for structural
elucidation of saponins is mainly based on the use of
spectroscopic techniques, including HRFABMS and
advanced 2D NMR experiments thus keeping the
material for further biological assays. Chemical
methods are only applied for stereostructure elucida-
tion of sugar moieties. 2D NMR methods have the
enormous advantage of to overcome the overlapping
of a large number of signals in the 1D NMR spectra of
saponins and to determine: the aglycone structure, the
number of sugar residues including their nature and
their configuration, the glycosylation site, and the
interglycosidic linkages (Lanzotti, 2005, 2012).
Table 2 lists the species from which saponins have
been extracted and characterized. The majority of
available studies focus on common, cultivated species
such as garlic (A. sativum), onion (A. cepa), leek (A.
ampeloprasum var. porrum), chinese onion (A. chin-
ense) and chives garlic (A. tuberosum). However,
studies on rare or wild species are also available (e.g.
A. cyrilii, A. leucanthum, A. minutiflorum; Table 2).
Concerning garlic, proto-eruboside B (11, Fig. 3)
was the first furostanol saponin isolated from the bulbs
(Matsura et al. 1988). The spirostanol analogue,
eruboside B (12, Fig. 3), has been obtained by
enzymatic hydrolysis of the furostanol derivative
proto-eruboside B. Later on, it has been reported from
fresh bulbs of garlic the isolation of two closely related
saponins, named proto-iso-eruboside B (13, Fig. 3)
and iso-eruboside-B (14, Fig. 3), the 25S epimers of
proto-eruboside B and eruboside B, respectively, and
their effects on platelet aggregation, blood coagulation
and fibrinolysis were examined by in vitro tests (Peng
et al. 1996).
Further studies from garlic bulbs led to the isolation
of a new furostanol saponin, named sativoside B1 (15,
Fig. 4) and characterization of the new proto-desga-
lactotigonin (16, Fig. 4) (Matsura et al. 1988). In the
same paper the structure elucidation of two new
steroidal glycosides, named sativoside R1 and sativ-
oside R2 (17 and 18, respectively, Fig. 4) have been
reported from garlic roots. The saponin composition of
AGE (aged garlic extract) have been studied that
Phytochem Rev

Table 2 List of saponins from the genus Allium and related biological activities. Note that only in few cases (18 out of 64) cytotoxic
activity was assessed
Species name Compounds Activity Reference

Allium aflatunense Five spirostanol saponins Cytotoxic Mimaki et al.

Allium ampeloprasum Six spirostanol saponins
Allium ampeloprasum var. porrum Four sapogenins
(sub. A. porrum)
Allium ampeloprasum var. porrum Six spirostanol and two
(sub. A. porrum) cholestanol saponins
Allium chinense Two spirostanol saponins and
one sapogenin
Allium jesdianum One spirostanol saponins
Allium leucanthum Seven spirostanol saponins
Allium macleanii Five spirostanol and one
cholestanol saponins
Allium macrostemon Nine furostanol saponins
Allium macrostemon Two furostanol saponins
Allium nigrum Eight spirostanol and two
cholestanol saponins
(1999a)
HL-60 (leukemia)
Cytotoxic Sata et al. (1998)
P388
Antifungal
Cytotoxic Carotenuto et al.
(1997)
J774 (reticulum cell sarcoma)
WEHI-164 (fibrosarcoma)
P 388 (leukemia)
IGR-1 (melanoma)
Cytotoxic Fattorusso et al.
(2000)
J-774 (reticulum cell sarcoma)
WEHI-164 (fibrosarcoma)
Cytotoxic Baba et al. (2000)
HeLa (cervical carcinoma)
Cytotoxic Mimaki et al.
(1999b)
HL-60 (leukemia)
CCRF-CEM (leukemia)
HOP-62 (lung cancer)
MCF-7 (breast cancer)
Cytotoxic Mskhiladze et al.
(2008a)
A549 (lung carcinoma)
DLD-1 (colon adenocarcinoma)
Cytotoxic Inoue et al. (1995)
HeLa (cervical carcinoma)
Cytotoxic Chen et al. (2007)
HepG2 (liver carcinoma)
R-HepG2 (liver carcinoma, drug
resistant)
MCF-7 (breast cancer)
NCI-H460 (lung carcinoma)
SF-268 (glioblastoma)
Cytotoxic Chen et al. (2009)
NCI-H460 (lung carcinoma)
SF-268 (glioblastoma)
Cytotoxic Jabrane et al.
(2011)
HT-29 (colorectal
adenocarcinoma)

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 Phytochem Rev

Table 2 continued
Species name Compounds Activity Reference

HCT-116 (colorectal carcinoma)

Allium schoenoprasum Four spirostanol saponins Cytotoxic Timité et al. (2013)
HCT-116 (Colorectal carcinoma)
HT-29 (Colorectal
adenocarcinoma)
Allium senescens Two spirostanol saponins Cytotoxic Inoue et al. (1995)
HeLa (cervical carcinoma)
Allium tuberosum One spirostanol saponin Cytotoxic Sang et al. (2002)
L-60 (leukemia)
Allium ursinum Two spirostanol saponins Cytotoxic Sobolewska et al.
(2006)
B16 (melanoma)
XC (sarcoma)
Antifungal
Allium vavilovii Four spirostanol saponins Cytotoxic Zolfaghari et al.
(2013)
J-774 (reticulum cell sarcoma)
WEHI-164 (fibrosarcoma)
Allium vavilovii Four furostanol saponins Cytotoxic Zolfaghari et al.
(2013)
J-774 (reticulum cell sarcoma)
WEHI-164 (fibrosarcoma)
Allium ampeloprasum var. porrum Four spirostanol saponins Antifungal Carotenuto et al.
(sub. A. porrum) (1999)
Fusarium culmorum
Allium cepa Three furostanol saponins Antifungal Lanzotti et al.
(2012a)
Alternaria alternata
Aspergillus niger
Botrytis cinerea
Fusarium oxysporum
Mucor sp.
Phomopsis sp.
Rhizoctonia solani
Sclerotium cepivorum
Trichoderma atroviride
Trichoderma harzianum
Allium leucanthum Five spirostanol saponins Antifungal Mskhiladze et al.
(2008b)
Yeast strains
Allium minutiflorum Two furostanol and three Antifungal Barile et al. (2007)
spirostanol saponins
Alternaria alternata
Alternaria porri
Botrytis cinerea
Fusarium oxysporum

123
Phytochem Rev

Table 2 continued
Species name Compounds Activity Reference

Fusarium oxysporum f.sp.

lycopersici
Fusarium solani
Pythium ultimum
Rhizoctonia solani
Trichoderma harzianum
Allium persicum Four furostanol, two Antifungal Sadeghi et al.
spirostanol and one (2013)
cholestanol
Aspergillus niger
Botrytis cinerea
Penicillium italicum,
Trichoderma harzianum
Allium sativum Ten furostanol and two Antifungal Lanzotti et al.
spirostanol saponins (2012b)
Botrytis cinerea
Trichoderma harzianum
Allium sativum One furostanol saponins Antifungal Matsura et al.
(1988)
Candida albicans
Allium vineale Nine spirostanol saponins Antifungal Chen and Snyder
(1989)
Penicillium expansum
Molluscicidal
Allium fistulosum Nine furostanol saponins Antihypoxic Lai et al. (2010)
Allium macrostemon Three furostanol saponins Antiplatelet Ou et al. (2012)
Allium sativum One furostanol and three Antiplatelet Peng et al. (1996)
spirostanol saponins
Allium cepa Eleven furustanol saponins Antispasmodic Corea et al. (2005)
Allium hirtifolium Five furostanol and four Antispasmodic Barile et al. (2005)
spirostanol saponins
Allium chinense Six spirostanol saponins ATPase inhibition Kuroda et al.
(1995)
Allium giganteum One spirostanol and two cAMP phosphodiesterase Mimaki et al.
furostanol saponins inhibition (1994)
Allium macrostemon Eight furostanol saponins Cellular Ca2? activity Chen et al. (2006)
Allium ampeloprasum One spirostanol saponin Haemolytic, anti-inflammatory, Adão et al. (2011)
gastroprotective
Allium aflatunense One spirostanol saponin Not assessed Kawashima et al.
(1991)
Allium albanum Five saponins Not assessed Ismailov et al.
(1976)
Allium albiflorus One saponin Not assessed Ismailov and Aliev
(1976)
Allium albopilosum Two spirostanol and four Not assessed Mimaki et al.
cholestanol saponins (1993)
Allium ascalonicum Four furostanol saponins Not assessed Kang et al. (2007)

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 Phytochem Rev

Table 2 continued
Species name Compounds Activity Reference

Allium atroviolaceum One sapogenin and one Not assessed Zolfaghari et al.
spirostanol saponin (2006)
Allium cepa var. tropeana Eight furostanol saponins Not assessed Dini et al. (2005)
Allium chinense Two furostanol saponins Not assessed Peng et al. (1996)
Allium cyrillii Two spirostanol saponins Not assessed Tolkacheva et al.
(2012)
Allium elburzense Eight furostanol and five Not assessed Barile et al. (2004)
spirostanol saponins
Allium erubescens One spirostanol saponins Not assessed Chincharadze et al.
(1980)
Allium fistulosum Five spirostanol saponins Not assessed Do et al. (1992)
Allium fistulosum Seven sapogenins Not assessed Lai et al. (2010)
Allium giganteum One spirostanol saponin Not assessed Kawashima et al.
(1991)
Allium giganteum One sapogenin Not assessed Khristulas et al.
(1970)
Allium karataviense Four spirostanol saponins Not assessed Vollerner et al.
(1978)
Allium nutans Two furostanol and two Not assessed Akhov et al. (1999)
spirostanol
Allium ostrowskianum One cholestanol saponin Not assessed Mimaki et al.
(1993)
Allium rotundum One furostanol and one Not assessed Maisashvili et al.
spirostanol saponin (2012)
Allium rubellum Four saponins Not assessed Ismailov et al.
(1976)
Allium schubertii One furostanol and three Not assessed Kawashima et al.
spirostanol saponins (1993)
Allium sphaerosephalon One furostanol saponin Not assessed Mimaki et al.
(1996)
Allium triquetrum Ten furostanol saponins Not assessed Corea et al. (2003)
Allium tuberosum Two spirostanol saponins Not assessed Sang et al. (1999a)
Allium tuberosum Three furostanol saponins Not assessed Sang et al. (1999b)
Allium tuberosum Four spirostanol, three Not assessed Sang et al. (2003)
furostanol, and one
cholestanol saponins
Allium tuberosum One spirostanol saponins Not assessed Zou et al. (2001)
Allium turcomanicum Five sapogenins Not assessed Pirtskhalava et al.
(1979)
Allium turcomanicum One spirostanol saponin Not assessed Pirtskhalava et al.
(1979)
Allium waldsteinii Three sapogenins and five Not assessed Gugunishvili et al.
saponins (2006)

123
Phytochem Rev
Fig. 3 Main saponins from garlic bulbs
allowed the isolation of saponins 19–35 (Fig. 5), two
of which (33 and 35, Fig. 5), based on new structures
(Matsuura 2001). This paper also demonstrated the
high stability of these saponin compounds during the
time and their ability to inhibit the cholesterol
absorption from the intestinal lumen in experimental
animals, and consequently to reduce the concentration
of plasma cholesterol.
Thus, saponins isolated from garlic as well as found
in related Allium species are mainly based on spirost-
anol and furostanol aglycon (Fig. 6) (Lanzotti et al.
2012a, b). Structurally, they are C27 sterols in which
cholesterol has undergone modifications to produce a
spiroketal. In particular, the spiroketal function is
derived from the cholesterol side-chain by a series of
oxygenation reactions affording hydroxylation at C-16
and at one of the terminal methyls, and then producing
a ketone function at C-22. This intermediate is
transformed into the hemiacetal, an unstable interme-
diate that undergoes glycosylation reaction at C-26
thus obtaining the spirostanol aglycon or further
reaction giving rise to the corresponding spiroketal,
that is the spirostanol aglycon. This can be also
obtained by hydrolysis of the furostanol aglycon with
the releasing of the sugar unit(s) at C-26.
The cholesterol aglycon has been only found in A.
ampeloprasum var. porrum and A. nigrum, while the
other skeletons are both present at almost the same level
(Lanzotti et al. 2012a, b). From the data in the literature
it seems that the spirostanol skeleton is typical of garlic
taxa, while the furostanol skeleton is typical for onion
taxa. Hydroxylation on the skeletal core has been
commonly found at position 2, 3, 5 and 6.
Antimicrobial activity of saponins
Saponins from Allium species has many biological
properties including antispasmodic, antifungal, hae-
molytic, anti-inflammatory, cholesterol-lowering, and
cytotoxic activity (Table 2). Surprisingly only a few
studies have investigated their antimicrobial proper-
ties of Allium saponins. Among these, Barile et al.
(2007) reported three saponins, named minutosides
A–C tested against several fungal plant pathogens,
including Botrytis cinerea, Fusarium oxysporum and
Rhizoctonia solani. In particular, minutoside B (36,
Fig. 7) was the major saponin plant tissue
(83.5 mg kg-1) and also showed the highest activity
in inhibiting spore germination and hyphal growth of
the tested fungi. Recent studies further reported that
several saponins from the common garlic var. Voghi-
era (Lanzotti et al. 2012a), and onion (Lanzotti et al.
2012b) have potent antifungal activity versus several
plant pathogens. As example, the chemical structures
of voghierosides A (37, Fig. 7) and ceposides B (38,
Fig. 7) have been reported in Figure. In addition, it has
been shown that the antifungal activity of ceposides
isolated from A. cepa against the plant pathogen
Botrytis cinerea and the biocontrol agent Trichoderma
harzianum can be synergically enhanced when they
are supplied in combination (Lanzotti et al. 2012a, b).
123
 Phytochem Rev

Fig. 4 Main saponins from

garlic bulbs and roots

Indeed, Allium species can produce a great diversity This contrasts with saponins from other plant species
of saponins that are stored in plant cells and have such as oat (Avena sativa) and tomato (Solanum
in vitro antifungal activity. However, their role in plant lycopersicum) for which the role in plant defense of
resistance against pathogens still has to be elucidated. avenacin and a–tomatine, respectively, has been

123
Phytochem Rev

clearly demonstrated (Morrisey and Osbourn 1999;

Martin-Hernandez et al. 2000). Bowyer et al. (1995)
reported that the fungus Gaeumannomyces graminis
var. avenae is able to infect oat because it produces the
enzyme avenacinase that detoxifies avenacins, the
antifungal oat saponins. To clarify the biological
significance of Allium saponins in plant defense, future
studies should assess if these compounds accumulate
in plant tissues at concentrations which can inhibit
pathogens in vivo, and identify the molecular mech-
anisms involved in their antimicrobial activity.

Cytotoxic activity of saponins

In the recent years a great number of papers concern-

Fig. 5 Main saponins from garlic aged extract (AGE)
ing the biological activity of saponins have been
published. Triterpene and steroid saponins have been
isolated from many plant species and tested for their
cytotoxicity against a wide range of cancer cell lines
(see the review by Podolak et al. 2010). Saponins from
species of the genus Allium have been all identified as
steroidal compounds and their biological activity has
been assessed in more than 60 cases (Table 2).
However, there is still a conspicuous number of
saponins from Allium species for which no biological

Fig. 6 Aglycon skeletons of Allium saponins and biosynthetic pathway

123

Fig. 7 Examples of
antimicrobial saponins
isolated from A.
minutiflorum, A. sativum
var.Voghiera, and A. cepa
activity has been assessed (Table 2). In about 15 cases,
Allium saponin cytotoxicity against various cancer cell
lines has also been shown (Sautour and Mitaine-Offer
2007). Spirostanol and furanostanol saponins from A.
leucanthum were assayed for cytotoxicity on cell lines
including lung adenocarcinoma (A549), colorectal
adenocarcinoma (DLD-1) and normal skin fibroblasts
(WS1). Results showed that only spirostanol saponins
were active against both tumor cell lines (Mskhiladze
et al. 2008a, b). The data reported evidenced that for
steroidal saponins the presence of sugar moieties is
important for the activity (Fig. 8). Two steroidal
saponins from A. macrostemon were assayed against
several human cancer cell lines, including MCF-7
(breast), NCI-H460 (lung), SF-268 (central nervous
system, CNS) and HepG2 (liver) (Chen et al.2009).
The two saponins showed different activities: one
(named 1 and based on a D25–27 furostanol pentagly-
coside structure) was active only towards the SF-268
cell line, while the other (named 2 and based on a
D20–22, D25–27 furostanol triglycoside structure) was
cytotoxic to both SF-268 and NCI H460 cell lines.
123
Phytochem Rev
Comparison of cytotoxity and structure of the two
saponins revealed that the presence of a double bond at
C25-C27 and a hydroxyl at C-12 in compound 1 and a
double bond at C20-C22 in compound 2 were
responsible for the observed selective cytotoxicity
(Fig. 8).
Cytotoxic activity of a mixture of two spirostanol
saponins from A. ursinum was assayed against cell
lines of melanoma B16, sarcoma XC and human
fibroblasts HSF (Sobolewska et al. 2006). The mixture
was found to be active against murine melanoma B16
and sarcoma XC, but showed no activity towards
human fibroblasts HSF at low concentrations.
Baba et al. (2000) showed that two spirostanol
saponins extracted from A. chinense, xiebai-saponin I
and laxogenin diglycoside, were strongly cytotoxic to
Hela cells. The study was conducted by measuring the
inhibition of the 12-O-tetradecanoylphorbol-13-acet-
ate-enhanced P-incorporation into phospholipids of
cells, a method very useful for screening compounds
with anticancer activity. The same paper reports that
the saponin laxogenin was proven to reduce the
Phytochem Rev
Fig. 8 Main structural elements increasing the cytotoxic activity of furostanol (left) and spirostanol (right) Allium saponins
average number of lung tumor induced by glycerol in
4-NQO-initiated mice. The data obtained suggested
that the structure of sugar chain might determine the
cytotoxic activity. Inhibitory effects on 12-O-tetra-
decanoylphorbol-13-acetate-stimulated 32Pi-incorpo-
ration into phospholipids of Hela cells were also
observed with steroidal saponins isolated from A.
macleanii and A. senescens (Inoue et al. 1995). Other
new spirostanol saponins isolated from leek (A.
ampeloprasum var. porrum (sub. A. porrum) were
tested for their cytotoxic activity on two different cell
lines (J-774, murine monocyte/macrophage, and
WEHI-164, murine fibrosarcoma) and showed a good
activity in reducing cell viability (Fattorusso et al.
2000). Among the tested saponins, high activity was
found for spirostanol saponins tetraglycosides with
2-OH or 6-OH groups (Fig. 8). It has been found
activity also for saponins based on cholestane bides-
moside structure. In addition, two sapogenins,
12-keto-porrigenin and 2,3-seco-porrigenin, isolated
from the organic extract of leek exhibited antiprolif-
erative activity on four tumor cell lines in vitro
(Carotenuto et al. 1999). In addition, the sapogenin
based on the rare secospirostane skeleton on ring A
showed higher activity on all tested cell lines.
Recently, a mixture of vavilosides and ascalonic-
oside extracted from A. vavilovii were subjected to
cytotoxic tests on two cell lines: J-774 (murine
macrophage) and WEHI-164 (murine fibrosarcoma)
(Zolfaghari et al. 2013). All saponins tested showed a
significant activity that increased with their concen-
tration. The most active compounds of the series were
vaviloside B1/B2, followed by ascalonicoside A1/A2,
and last by vaviloside A1/A2. Since these compounds
have the same aglycone, it appears that the sugar
portion of the molecules may modulate the activity.
The substitution of a galactose unit (as found in
vaviloside A1/A2 with a xylose unit (as found in
vaviloside B1/B2) increases the cytotoxic activity.
The substitution of one rhamnose with one glucose,
apart from their different position, seems also to
produce a positive effect on the activity. Jabrane et al.
(2011) isolated six (some in epimeric mixtures)
spirostane and cholestane saponins from A. nigrum
and evaluated their cytotoxicity against the human
colon cancer (HCT 116 and HT-29) cell lines. Results
showed that only two out of all the isolated com-
pounds, based on a tetraglycosidic spirostanol skele-
ton bearing OH groups at C-2 and C-6 were active
against the cells (Fig. 8), in agreement with previous
findings. Similarly, out of twelve steroidal isolated
from bulbs of A. karataviense, only one exhibited
cytostatic activity against human promyelocytic leu-
kemia HL-60 cells (Mimaki et al. 1999a,b). In a recent
study (Timité et al. 2013), a number of steroidal
saponins were isolated from A. schoenoprasum and 4
of them assayed for cytotoxic activity against the HCT
116 and HT-29 human colon cancer cell lines. The
results showed that two were very potent cytotoxic
compounds, while one was moderately active and
another one inactive on both cell lines. The authors
hypothesize that the presence of a ketone function at
the C-6 of the aglycon moiety may be responsible for
the lack of activity.
Mimaki et al. (2001) examined the cytotoxic
activities of steroidal saponins from Liliaceae plants
against HL-60 human promyelocytic leukemia cells.
Results showed that activities of these compounds
were depending on the monosaccharides present in the
sugar moieties and on their sequences. For example,
the saponin diosgenin b-D-glucopyranoside did not
show any cytotoxic activity, but the attachment of an a-
L-rhamnopyranosyl group at the C-2 of the glucopyr-
anosyl moiety caused the appearance of activity. The
123

addition of an a-L-rhamnopyranosyl, an a-L-arabino-
furanosyl or a b-D-glucopyranosyl, with the exception
of a b-D-galactopyranosyl, to C-3 or C-4 of the inner
glucosyl moiety, did not influence the activity. The
attachment of a b-D-galactopyranosyl at C-3 of the
glucopyranosyl residue increased the activity. The
authors found that the structure of the aglycons also
affects the activity of diosgenin. The introduction of an
hydroxyl group at C-17 of the aglycon slightly reduced
the cytotoxicity of active saponins, while the same
group at C-27 decreased the activity to a much greater
extent. Furostanol saponins, which usually do not show
cytotoxic activity to cancer cells, when they have an a-
L-rhamnopyranosyl-(1?2)-b-D-glucopyranosyl or an
a-L-rhamnopyranosyl-(?2)-[a-L-rhamnopyranosyl-
(1?4)]-b-D-glucopyranosyl at C-3 of the aglycon
become active against HL-60 cells.
The mechanism of action of saponins from plants
against tumoral cell lines have been largely investi-
gated (Podolak et al. 2010). Cytotoxicity of steroidal
saponins, initially, has been associated to their deter-
gent effect on the cell membranes (Furuya et al. 2000).
In the past ten years, several other mechanisms have
been reported including apoptosis (Sun et al. 2009, Li
et al. 2008, Xu et al. 2009, Wang et al. 2008), cell cycle
arrest (Sun et al. 2009, Liu et al. 2005),, autophagy
(Ellington et al. 2005, Xu et al. 2007), inhibition of
angiogenesis (Wang et al. 2008, Tian et al. 2005),
disintegration of cytoskeleton (Li et al. 2008), and
inhibition of metastasis (Tian et al. 2005, Man et al.
2009). Unfortunately, mechanisms of action of sapo-
nins from Allium species have not been much studied.
To our knowledge, only one paper (Candra et al. 2002)
investigated about the cytotoxic mechanism of sapo-
nins from plants belonging to the family of Liliaceae
including some Allium species. These authors reported
that these saponins were able to cause death of mouse
lymphocytic leukemia L1210 cells by inducing apop-
tosis. Further research is needed to completely under-
stand the mechanisms of action of Allium saponins and
how they correlate to those of saponins from other
plant species.
Conclusions
Garlic and the related Allium species are among the
oldest phytomedicine, used as antibacterial, antimy-
cotic, hypoglycemic, hypotensive, hypocholesterolemic,
123
Phytochem Rev
antiatherosclerotica, antithrombotic cytotoxic drugs.
Responsible of their pungent taste and also of some of
these bioactivities are volatile sulphur organic com-
pounds that have been studied in detail and have shown to
be chemically reactive. They easily give rise to several
organosulphur compounds, mainly disulphides and tri-
sulphides, whithout loss of pharmacological activities.
In addition, these plants also have been shown to
contain spirostanol, furostanol and cholesterol saponin
compounds that have recently received an increasing
scientific attention because of their antimicrobial,
antifungal, antiplatelet aggregating, and cytotoxic
activities. This class of compounds has the advantage
of being more stable to food processing and cooking
compared to the volatile compounds. Cytotoxicity of
steroidal saponins from plants has been initially
associated to their detergent effect on cell membranes,
while in the recent years several other mechanisms
have been reported including apoptosis, cell cycle
arrest, autophagy, inhibition of angiogenesis, disinte-
gration of cytoskeleton and inhibition of metastasis.
However, studies on cytotoxic mechanisms of sapo-
nins from Allium species are not available. Only one
report shows that saponins from plants of the family
Liliaceae, including Allium species, are able to cause
death of cancer cells by inducing apoptosis.
Future studies should focus on the mechanism of
action of garlic and related Allium compounds and the
relationship between chemical structure and activity
(SAR) but also on clinical tests to evaluate the
potential effects of the isolated metabolites in human
health.
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