Aspiritin

International Journal of
Molecular Sciences
Review
Anticancer Potential of Furanocoumarins:
Mechanistic and Therapeutic Aspects
Salman Ahmed 1 , Haroon Khan 2 , Michael Aschner 3 , Hamed Mirzae 4 , Esra Küpeli Akkol 5
and Raffaele Capasso 6, *
1 Department of Pharmacognosy, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi,
Karachi 75270, Pakistan; salmanahmed@uok.edu.pk
2 Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan;
haroonkhan@awkum.edu.pk
3 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10463, USA;
michael.aschner@einsteinmed.org
4 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences,
Kashan University of Medical Sciences, Kashan 8715973474, Iran; mirzaeih911h@mums.ac.ir
5 Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Etiler, 06330 Ankara, Turkey;
esrak@gazi.edu.tr
6 Department of Agricultural Sciences, University of Naples Federico II, Via Università 100, 80055 Portici, Italy
* Correspondence: rafcapas@unina.it; Tel.: +39-081-678664

Received: 9 July 2020; Accepted: 3 August 2020; Published: 6 August 2020
Abstract: Cancer is one of the most extreme medical conditions in both developing and developed
countries around the world, causing millions of deaths each year. Chemotherapy and/or radiotherapy
are key for treatment approaches, but both have numerous adverse health effects. Furthermore,
the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden
of cancer overall requires novel efficacious treatment modalities. Natural medications offer feasible
alternative options against malignancy in contrast to western medication. Furanocoumarins’ defensive
and restorative impacts have been observed in leukemia, glioma, breast, lung, renal, liver, colon,
cervical, ovarian, and prostate malignancies. Experimental findings have shown that furanocoumarins
activate multiple signaling pathways, leading to apoptosis, autophagy, antioxidant, antimetastatic,
and cell cycle arrest in malignant cells. Additionally, furanocoumarins have been shown to have
chemo preventive and chemotherapeutic synergistic potential when used in combination with other
anticancer drugs. Here, we address different pathways which are activated by furanocoumarins and
their therapeutic efficacy in various tumors. Ideally, this review will trigger interest in furanocoumarins
and their potential efficacy and safety as a cancer lessening agents.
Keywords: furanocoumarin; apoptosis; autophagy; metastasis; cell cycle arrest
1. Introduction
Cancer exacts one of the greatest medical tolls on humankind, requiring a proactive procedure for
prevention and treatment. An enormous number of patients succumb to cancer every year. It is one of
the chief reasons for mortality around the world, and the number of cases is continually expanding
and estimated to reach 21 million by 2030. The lack of efficient anticancer treatments remains a clinical
problem [1,2]. Chemotherapy and/or radiotherapy are the main clinical approaches to cancer treatment,
yet both have documented adverse effects [3–6]. Cancer treatment affects not only rapidly multiplying
cancerous cells but also normal body cells (bone marrow, gastrointestinal tract (GIT), and hair follicles);
therefore, these treatments may give rise to severe adverse symptoms. Moreover, quick disposal and
Int. J. Mol. Sci. 2020, 21, 5622; doi:10.3390/ijms21165622 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2020, 21, 5622 2 of 20
widespread distribution of the medications in cancer-free organs requires high dosing, which may lead
to incremental adverse reactions. Resistance towards malignant growth is another restriction.
Restorative plants have been utilized previously. Phytopharmaceuticals primarily target malignant
growth, and hence, they are the most appropriate contender for anticancer medications [1,2]. Nowadays,
significant efforts have improved the efficacy of natural anticancer drugs with the appearance of
encouraging strategies [7,8].
Furanocoumarins are phytochemicals that have been utilized for quite a while. The Atharva-Veda,
the Indian hallowed book, portrays the Psoralea corylifolia poultice, and the old Egyptians utilized Ammi
majus for leukoderma (vitiligo). In 1838, 5-Methoxypsoralen (5-MOP) was the first furanocoumarin
isolated from Citrus bergamia oil by Kalbrunner [9]. Furocoumarins are formed by coumarin and a furan
ring combination, resulting in angular or linear isomers depending on the furan ring position. Angelicin
and psoralen are basic furocoumarins that act as precursors for angular and linear furocoumarins,
respectively. These compounds are, for the most part, biosynthesized by phenylpropanoid and
the mevalonic pathways. Furocoumarins are produced in plants of Apiaceae and Rutaceae as
well as in Asteraceae, Caryophyllaccae, Fabaceae, Moraceae, and Salvadoraceae for defense against
insects, bacterial and fungal predators. They provide antimicrobial and insecticidal activity and
behave as natural pesticides [10]. Furocoumarins have promising therapeutic prospects, such as
analgesic, anticonvulsive, anticoagulant, hypotensive, antidepressants, antibacterial, antifungal,
antiviral, anti-inflammatory, antiallergic [11,12], antioxidants [13], and inhibitors of human carbonic
anhydrase isozymes [14], against skin diseases [15,16], hyperproliferative disorders [17,18] and as an
anticancer [19]. This review is aimed at evaluating the literature on the anticancer potential of various
furanocoumarins through different underlying mechanisms and thereof therapeutic/clinical status.
2. Chemistry of Furocoumarins
The exact molecular mechanism of such an activity relies upon the chemical structure of
furanocoumarins, which depends on the furan ring and coumarin backbone combination in an
angular or linear structure just as the type, location, and the number of the substituents attached [11].
The CH3 presence at C5 improves the tumor properties of psoralen and 5-MOP, paying little heed to the
substituent location. The substitution of the methoxy group with an isopentenyloxy moiety in the C5
position prompted abatement in the pro-apoptotic properties of the compound [20–22]. Angelicin is the
most straightforward angular furanocoumarin and it displays counter cancer properties. Analogous to
linear furocoumarins, angular analogs can be substituted with a methoxy or isopentenyloxy group.
Methoxy subordinates of angelicin incorporate isobergapten and sphondin. Isobergapten, for example,
5-methoxyangelicine, is a linear isomer of bergapten with a methoxy group joined to the fifth (C5)
carbon atom. Thus, sphondin (6-methoxyangelicin) can be considered as an angular analogue of
xanthotoxin. The thing that matters is, be that as it may, that the methoxy group is appended to the C6
position in 6-methoxyangelicin and to the C8 atom in the 8-MOP [11].
Furanocoumarins’ defensive and restorative properties have been observed in leukemia, glioma,
breast, lung, renal, liver, colon, cervical, ovarian, and prostate malignancies. Apoptosis, autophagy,
antioxidant, cell cycle capture, Nuclear Factor Kappa-light-chain-enhancer of activated B cells
(NF-κB) inactivation, Phosphatidylinositol 3-kinase/RAC-α Serine/Threonine-Protein Kinase (PI3K/Akt)
inhibition, and p53 modulation incorporate mechanistic insight (Table 1; Figure 1). In this article,
we have reviewed the experimental data showed the role of furanocoumarins for cancer prevention
and treatment.
Int. J. Mol. Sci. 2020, 21, 5622 3 of 20
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 4 of 22
Table 1. Anticancer effects of furanocoumarins in the different reported studies.
Table 1. Anticancer effects of furanocoumarins in the different reported studies.
Table 1. Anticancer effects of furanocoumarins
In Vitro In Vivo in the different reported studies.
Dietary Sources
Furanocoumarins In Vitro Cytotoxic In Vivo
Experimental Anticancer Mechanisms References
Dietary Sources
[2–4] Cell Lines Dose
Furanocoumarins Cytotoxic
Concentration Experimental
In VitroModel Anticancer Mechanisms
In Vivo References
[2–4] Cell
Dietary Sources Lines
[2–4] Dose
Furanocoumarins IC30Concentration
= 27.8 µM; IC50 = Model Anticancer Mechanisms References
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW HeLa and SiHa Cell Lines — 4 of 22 —
Cytotoxic Concentration ↑, G1/G0 arrest
Atg3,7 and 12-5Model
Experimental [5]
Dose
IC 30 = 38.2
27.8 µM; IC50 =
µM
HeLa and SiHa — — Atg3,7 and 12-5 ↑, G1/G0 arrest [5]
38.2 µM NF-κB inactivation G2/M phase arrest,
HeLa and SiHa IC30 = 27.8 µM; IC50 = 38.2 µM — — Atg3,7 and 12-5 ↑, G1/G0 arrest [5]
Table 1. Anticancer effects of furanocoumarins in the different reported studies. ↓, cyclin E1 ↓,
NF-κB inactivation
cyclinB1 G2/M phase↓;arrest,
andCdc2 Bcl2 ↓;
A549 (NSCLC) IC50~ 50 µmol — — cyclinB1 ↓, caspase
cyclin E13,9 ↓,↑, Bax↑ ↓; Bcl2 ↓;
andCdc2 [6] NF-κB inactivation G2/M phase arrest,
In Vitro In Vivo
Dietary Sources A549 (NSCLC) IC50~ 50 µmol — — JNK ↑,3,9
caspase ERK↑, Bax↑
↑; [6] cyclinB1 ↓, cyclin E1 ↓, and Cdc2 ↓; Bcl2 ↓;
Furanocoumarins Cytotoxic Experimental Anticancer Mechanisms References
[2–4] Cell Lines A549 (NSCLC) IC50 ~ 50 µmol Dose MMP2,MMP9 — ↑,↓,ERK
JNK ↑;
E-cadherin ↑ — caspase 3,9 ↑, Bax↑ [6]
Concentration Model
SH-SY5Y IC50 = 49.56µM — — caspase 3,9 ↑, Bcl-2 ↓,↓,Bcl-xL↓,
MMP2,MMP9 E-cadherin ↑
and Mcl-1↓ [7] JNK ↑, ERK ↑;
SH-SY5Y IC30 =5027.8 µM; IC50 = 3,9 ↑,and ↓, ↑,
HeLa and SiHa IC50 =ICangelicin= 49.56µM
(50–100 —
— —
— caspase
Atg3,7 Bcl-2
12-5 Bcl-xL↓,
G1/G0 and arrestMcl-1↓ [7]
[5] MMP2, MMP9 ↓, E-cadherin ↑
Parsnip 38.2 µM
Parsnip Caki ICµM)
50 = angelicin
and TRAIL (50–100
(50 — — caspase 3↑, c-FLIP ↓ [8]
Parsnip
Caki SH-SY5Y
µM) and TRAIL (50
ng/mL) IC50—= 49.56 µM — — 3↑,G2/M
NF-κB inactivation
caspase c-FLIP phase
↓ arrest, —[8] caspase 3,9 ↑, Bcl-2 ↓, Bcl-xL↓, and Mcl-1↓ [7]
cyclinB1 ↓, cyclin E1 ↓, andCdc2 ↓; Bcl2 ↓;
IC50 ng/mL)= 90 ± 6.565 IC50 = angelicin (50–100 µM)
Angelicin HepG2
A549 and
(NSCLC) IC 50~ 50 µmol — — caspase 3,9 ↑, Bax↑ [6]
Angelicin IC50
(HepG2); Caki =6090±±4.256
6.565µM — — inhibition,Bcl-2↓ — caspase 3↑, c-FLIP ↓ [8]
Angelicin HepG2
Huh-7and and TRAIL (50 ng/mL)— PI3K/Akt
JNK ↑, ERK ↑;
[9]
(HepG2); 60 ± 4.256 µM
(Huh-7) — — PI3K/Akt inhibition,Bcl-2↓ [9]
Huh-7 MMP2,MMP9 ↓, E-cadherin ↑
(Huh-7) = 90 ±
IC50Mouse 6.565 (HepG2);
liver
SH-SY5Y HepG2 ICand Huh-7
50 = 49.56µM — µM (Huh-7)— — ↓, Bcl-xL↓, and Mcl-1↓
caspase 3,9 ↑, Bcl-2 —[7] PI3K/Akt inhibition, Bcl-2↓ [9]
60 ± 4.256
Mouse
xenograft liver
model 50 mg/kg cancer cell growth ↓;
— IC50 = angelicin — (50–100 [9]
Parsnip xenograft
(BALB/c-nu/nu model 50 mg/kg
(16 days) cancer cell growth
p-VEGFR ↓ ↓;
— µM) and— Mouse caspase
liver xenograft [9] cancer cell growth ↓;
Caki
— TRAIL (50 —
(BALB/c-nu/nu
mice) — (16 —
days) p-VEGFR ↓ ↓
3↑, c-FLIP
50 mg/kg [8]
(16 days) [9]
ng/mL) model (BALB/c-nu/nu mice) p-VEGFR ↓
mice) EMT inhibition, JNK ↑; PI3K ↓, Akt↓, and
A549, H1299 IC
IC50 50 = = 50–100 µM
90 ± 6.565 — — [10]
Angelicin HepG2 and EMT inhibition, mTOR JNK ↑; PI3K
kinases ↓ ↓, Akt↓, and EMT inhibition, JNK ↑; PI3K ↓, Akt↓,
A549, H1299 IC50 =H1299
A549,
(HepG2); 50–100 µMµM
60 ± 4.256 IC50— —= 50–100 µM — — PI3K/Akt — inhibition,Bcl-2↓
mTOR
NF-κB inactivation, kinases
MMP9 ↓ ↓, STAT3 — [10]
[9] [10]
Huh-7
U87 and U251 IC50(Huh-7)
= 2–10 µM — — [11] and mTOR kinases ↓
NF-κB inactivation,
inhibition, MMP9 ↓, STAT3
Rac1 inactivation
U87 and U251 IC50 = 2–10 µM Mouse — liver — [11] NF-κB inactivation, MMP9 ↓, STAT3
HT-1080 U87ICand 50 = 5–50
U251 µM IC50 — = 2–10 µM — inhibition,
NF-κB — Rac1 MMP2,MMP9↓
inactivation; inactivation —[12] [11]
Carrot, cumin, dill, xenograft model 50 mg/kg cancer cell growth ↓; inhibition, Rac1 inactivation
HT-1080
— IC50 = 5–50— µM — — NF-κBcaspase-3,8,9↑; PARP ↑;
inactivation; MMP2,MMP9↓ [12]
[9]
Carrot, cumin, dill,
fig, grapefruit, (BALB/c-nu/nu (16 days) p-VEGFR ↓
↑;
↓, cyclin
50 = 5–50 µM
fig,
Carrot,
grapefruit,
lemon, lime,
cumin, dill,and
HT-29 fig,RKO IC50 = 12.5 µM
HT-1080 —
ICmice) — G2/M phase caspase-3,8,9↑;
arrest,
— cyclinA PARP B1↓, —[13] NF-κB inactivation; MMP2, MMP9↓ [12]
grapefruit, lemon, lime,RKO
HT-29 and IC50 = 12.5 µM — — G2/M phase arrest, andCdc2 ↓
cyclinA ↓, cyclin B1↓, [13]
lemon,
orange, lime,
parsley, EMT inhibition, JNK ↑; PI3K ↓, Akt↓, and caspase-3,8,9↑; PARP ↑;
orange, G2/M phase arrest, andCdc2
cyclinA ↓ ↓, cyclin B1↓,
Bergamottin orange, parsley,parsley,
parsnip parsnip
A549,
A549
H1299
(NSCLC)
IC50 = 50–100 µM — —
kinases ↓
[10]
Bergamottin
HT-29ICand 50 = 50 µM
RKO IC— 50 = 12.5 µM
— mTOR
G2/M phase arrest,—andCdc2 cyclinA↓ ↓, cyclin B1↓, —[14] G2/M phase arrest, cyclinA ↓, cyclin B1↓, [13]
Bergamottin parsnip A549 (NSCLC) IC50 = 50 µM — — NF-κB inactivation, MMP9 ↓, STAT3 [14]
U87 and U251 IC50 = 2–10 µM Mouse —lung — andCdc2 ↓ [11] and Cdc2 ↓
100 mg/kg inhibition, Rac1 inactivation
— — Mouse lung
xenograft model ↓ cancer cell growth [14]
HT-1080 IC(NSCLC)
50 = 5–50 µM — = 50 µM 100 mg/kg
(18 days)
— NF-κB inactivation; G2/M phase arrest, cyclinA ↓, cyclin B1↓,
Carrot, cumin, dill, — A549 — ICnude
xenograft
(BALB/c 50 model
mice) — cell MMP2,MMP9↓
↓ cancer growth —[12]
[14] [14]
(18 days) caspase-3,8,9↑; PARP ↑; and Cdc2 ↓
fig, grapefruit, (BALB/c nude mice) G2/M phase arrest,cyclin E ↓, Cdk2
Anise, carrot, HT-29 and RKO IC50 = 12.5 µM — — G2/M phase arrest, cyclinA ↓, cyclin B1↓, [13]
lemon, lime, DLD-1 and LoVo IC50 = 30 and 50 µM — — Mouse
G2/M phase
inhibition; lung xenograft
AKTarrest,cyclin
inhibition; p53 E ↓,↑,Cdk2
p21↑, [15]
Anise, carrot,
caraway, celeriac,
DLD-1 and LoVo
—
IC50 = 30 and 50 µM —
— — inhibition;
andCdc2 ↓
AKTPTEN↑inhibition;
100 mg/kg[15]
p53 ↑, p21↑,
(18 days) ↓ cancer cell growth [14]
orange, parsley, model (BALB/c nude mice)
Bergamottin caraway,
celery, celeriac,
coriander, G2/M phase arrest, cyclinA ↓, cyclin B1↓,
parsnip A549 (NSCLC) IC50 = 50 µM — — G1-phase phase arrest, P53 ↑; AKT
PTEN↑ [14]
celery,
cumin,coriander,
dill, fig, MCF-7 IC50 = 50 µM — — andCdc2 ↓ [16] G2/M phase arrest, cyclin E ↓, Cdk2
G1-phase phase arrest, P53 ↑; AKT
inhibition
50 =
cumin, dill,
grapefruit, fig,
lemon, MCF-7 DLD-1 IC50 = 50 µM — lung — [16] inhibition; AKT inhibition; p53 ↑, p21↑,
IC50 and = 25–50LoVomM ICMouse —30 and 50 µM 100 —mg/kg G2/M phase— inhibition
arrest, Cdk1 inhibition —[17] [15]
grapefruit,
lime, orange,lemon, Hep-G2
— — xenograft model ↓ cancer cell growth [14] PTEN↑
IC5050 == 25–100µM
IC 25–50 mM —
— (18——
days) G2/M phase
G2-M phase arrest,
arrest, P53
Cdk1 ↑ and P21 ↑
inhibition [17]
[18]
Bergapten or lime, orange,
parsley, parsnip, Hep-G2 (BALB/c nude mice)
IC79.1
50 = 25–100µM
± 2.8% — — G2-M phase arrest, P53 ↑ and P21 ↑ [18] G1-phase phase arrest, P53 ↑;
Bergapten or
5-Methoxypsoralen (5-MOP) parsley, parsnip,
turnip A549 (NSCLC) MCF-7 IC— = 50 µM — G2/M G1-phase
phase — arrest, P53
arrest,cyclin E ↑↓, Cdk2 —[19] [16]
Anise, carrot, 79.1
(50 ±µM)
2.8% 50
5-Methoxypsoralen (5-MOP) turnip A549 (NSCLC)
DLD-1 and LoVo IC50 = 30 and 50 µM — — G1-phase
inhibition; arrest, P53
AKT inhibition; p53↑ ↑, p21↑, [19]
[15] AKT inhibition
caraway, celeriac, (50 µM)
Anise, carrot, caraway,
celery, coriander, IC50 = 25–50 mM — PTEN↑ — G2/M phase arrest, Cdk1 inhibition [17]
celeriac, celery, coriander, Hep-G2 G1-phase phase arrest, P53 ↑; AKT
cumin, dill, fig, MCF-7 IC50 = 50 µM IC50—= 25–100 µM — —inhibition —[16] G2-M phase arrest, P53 ↑ and P21 ↑ [18]
cumin,
grapefruit, dill, fig, grapefruit,
lemon,
lemon, lime, orange,Hep-G2
parsley, IC50 = 25–50 mM —
79.1 ± 2.8% — G2/M phase arrest, Cdk1 inhibition [17]
lime, orange,
parsnip, turnip A549 IC50(NSCLC)
= 25–100µM — — G2-M phase —arrest, P53 ↑ and P21 ↑ —[18]
Bergapten
Bergapten or or
5-Methoxypsoralen parsley, parsnip, (50 µM)
79.1 ± 2.8% G1-phase arrest, P53 ↑ [19]
5-Methoxypsoralen (5-MOP)
(5-MOP) turnip A549 (NSCLC) — — G1-phase arrest, P53 ↑ [19]
(50 µM) 74.5 ± 3.1%
NCI-H460 — —
(50 µM)
PTEN ↑, Beclin1 ↑, PI3KIII ↑, UVRAG ↑,
MCF7 and ZR-75 50 µM — — [20]
AMBRA, LC3-I to LC3-II
HepG2 50 mM — — PI3K/AKT inhibition, LXR (α and β)↑
NDEA induced liver cancer 25 and 50 mg/kg (14 [21]
— — ↓ cancer cell growth
(Wistar rats) days)
74.5 ± 3.1%
NCI-H460 — —
(50 µM)
PTEN ↑, Beclin1 ↑, PI3KIII ↑, UVRAG ↑,
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW MCF7 and ZR-75 50µM — 5 of 22 — [20]
Int. J. Mol. Sci. 2020, 21, 5622 AMBRA, LC3-I to LC3-II 4 of 20
74.5 ± 3.1% NDEA induced 25 and
NCI-H460 — — [21]
— (50— µM) liver cancer 50 mg/kg ↓ cancer cell growth
(Wistar rats) (14 days) PTEN ↑, Beclin1 ↑, PI3KIII ↑, UVRAG ↑,
MCF7 and ZR-75 50µM — Table 1. Cont.
—
AMBRA, LC3-I to LC3-II
[20]

Carrot, grapefruit, In Vitro
NDEA induced 25 and In Vivo
Furanocoumarins Dietary Sources [2–4] G1-phase arrest; caspase 3,9 ↑, Bax↑, Bcl2 [21] Anticancer Mechanisms References
lemon, lime, MCF-7
— IC50 = —
52.2 µM liver —
cancer —
50 mg/kg ↓ cancer cell growth [22]
Cell Lines Cytotoxic Concentration ↓,MMP2 ↓,MMP9
Experimental ↓,cyt c release ↑
Model Dose
parsley, parsnip (Wistar rats) (14 days)
Bergaptol
Carrot, grapefruit,
Carrot, G1-phase arrest; caspase 3,9 ↑, Bax↑, Bcl2 G1-phase arrest; caspase 3,9 ↑, Bax↑, Bcl2
lime, grapefruit,MCF-7
lemon,
50 = 52.2 µM
lemon, IC50 = 52.2 µM
MCF-7 IC— — — [22]
— [22]
↓,MMP2 ↓,MMP9 ↓,cyt c release ↑ ↓,MMP2 ↓, MMP9 ↓, cyt c release ↑
parsley,lime,
parsnipparsley, parsnip
HCT-15 IC50 = 18.1 ± 0.3 µg·mL−1 — —
Bergaptol
Bergaptol
A549 (NSCLC)
HCT-15 IC5050==14.3
IC 18.1 ± 0.2
0.3 µg·mL−1 — —
HCT-15 IC50 = 18.1 ± 0.3 µg·mL−1 — —
SK-OV-3 IC50 = 20.2 ± 0.3 µg·mL−1 — —

Lemon ↓ cell viability [23]
A549 (NSCLC) A549 (NSCLC)
IC50 =14.3 ± 0.2 µg·mL−1 IC50 =14.3
— ± 0.2 µg·mL−1
— — —
Lemon SK-MEL-2 IC50 = 21.2 ± 0.3 µg·mL −1 — — ↓ cell viability [23]
SK-OV-3 IC50 = 20.2 ± 0.3 µg·mL−1 — —
SK-OV-3 IC50SK-MEL-2
= 20.2 ± 0.3 µg·mL−1 IC50 = 21.2
— ± 0.3 µg·mL−1
— — —
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW
Byakangelicol 6 of 22
Int. J. Mol.Byakangelicol
Sci. 2020, 21, x FOR PEER REVIEW XF498 IC50 = 28.4 ± 0.3
6 ofµg·mL
22 −1 — —
Lemon SK-MEL-2 IC50 = 21.2 ± 0.3 µg·mL−1−1 — — ↓ cell viability [23]
HCT-15 IC50 = 7.0 ± 0.2 µg·mL — —
A549HCT-15
(NSCLC) IC5050 == 6.8
IC 7.0 ±± 0.1
0.2 µg·mL
µg·mL−1−1 —
— —
—
A549 (NSCLC)
SK-OV-3 IC5050 == 8.8
IC 6.8 ±± 0.2
0.1 µg·mL
µg·mL−1−1 —
— —
—
XF498 IC50 = 28.4 ± 0.3 µg·mL−1−1 — —
Byakangelicol SK-OV-3
SK-MEL-2 IC5050 == 8.8
IC 8.8 ±± 0.2
0.2 µg·mL
µg·mL−1 —
— —
—
SK-MEL-2 IC50 = 8.8 ± 0.2 µg·mL−1 — —
HCT-15 IC50 = 7.0 ± 0.2 µg·mL−1 — —
XF498 IC50 = 28.4 ± 0.3 µg·mL−1 — —

Lemon Lemon ↓ cell viability [23] ↓ cell viability [23]
Lemon ↓ cell viability [23]
XF498 IC50 = 7.2 ± 0.3 µg·mL −1 — —
XF498 IC50 = 7.2 ± 0.3 µg·mL−1 — —
A549 (NSCLC) IC50 = 6.8 ± 0.1 µg·mL−1 — —
SK-OV-3 IC50 = 8.8 ± 0.2 µg·mL−1 — —
SK-MEL-2 IC50 = 8.8 ± 0.2 µg·mL−1 — —
Cnidicin
Cnidicin
Cnidicin
XF498 IC50 = 7.2 ± 0.3 µg·mL−1 — —
OH
OH
O
O
HO
HO NF-κB inactivation
Feroniella lucida NF-κB↑,inactivation
Feroniella A549 0.25 mM — — Atg5 ↑, Beclin1 mTOR inactivation [24] NF-κB inactivation
rootslucida Atg5 ↑, Beclin1
O A549
Feroniella lucida roots
roots
0.25 mM
A549 —
0.25 mM — — ↑,tomTOR
LC3-I LC3-IIinactivation [24]
— Atg5 ↑, Beclin1 ↑, mTOR inactivation [24]
O LC3-I to LC3-II LC3-I to LC3-II
O
O O O
OA
Feroniellin O
Feroniellin A
Feroniellin A
Fructus
Fructus A549 IC50 = 65.28 ± 5.36 µM — — P53 ↑,Bax↑, Bcl2 ↓,caspase 3 ↑ [25]
liquidambaris A549 IC50 = 65.28 ± 5.36 µM — — P53 ↑,Bax↑, Bcl2 ↓,caspase 3 ↑ [25]
OH
O
HO
NF-κB inactivation
Feroniella lucida
A549 0.25 mM — — Atg5 ↑, Beclin1 ↑, mTOR inactivation [24]
roots
Int. J. Mol. Sci.O 2020, 21, 5622 LC3-I to LC3-II 5 of 20
O
O O Table 1. Cont.
Feroniellin A
In Vitro In Vivo
Furanocoumarins Dietary Sources [2–4] Anticancer Mechanisms References
Cell Lines Cytotoxic Concentration Experimental Model Dose
Fructus
Fructus liquidambaris
A549
A549
IC50 = 65.28 ± 5.36 µM
IC50 =—
65.28 ± 5.36 µM— —
P53 ↑,Bax↑, Bcl2 ↓,caspase 3 ↑
—
[25]
P53 ↑,Bax↑, Bcl2 ↓, caspase 3 ↑ [25]
liquidambaris
Furanocoumarin A
Furanocoumarin A PEER REVIEW
Int. J. Mol. Sci. 2020, 21, x FOR 7 of 22
promoting G1-phase arrest;
SGC-7901 IC50 = 62.6 µM — — [26]
promoting G1-phase arrest; PI3K/Akt/m-TOR signaling ↓
SGC-7901 IC50 = 62.6 µM — — [26]
PI3K/Akt/m-TOR signaling ↓
G1-phase arrest; P53 ↑ and P21 ↑; caspase
HT-29 IC50 = 78 µM — P53 ↑ and P21 ↑; caspase
G1-phase arrest; — [27]
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW HT-29 IC50 = 78 µM — 7 of 22 — [27] 3,7 ↑; Bcl2 ↓
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 7 of 22 3,7 ↑; Bcl2 ↓
caspase 3,9 ↑; cyt c release ↑; Bcl2 ↓,PARP caspase 3,9 ↑; cyt c release ↑; Bcl2 ↓,
HL-60 HL-6010 µM —10 µM — promoting—cleavage
G1-phase arrest; [28]
— [28]
SGC-7901 IC50 = 62.6 µM — — promoting G1-phase arrest; [26] PARP cleavage
H23
SGC-7901 IC1050 =µg/mL
62.6 µM — — PI3K/Akt/m-TOR Mcl-1↓ ↓
P53 ↑,Bax↑, signaling [29]
[26]
H23 imperatorin 10 µg/mL PI3K/Akt/m-TOR
G1-phase arrest;—P53 ↑ andsignaling ↓
P21 ↑; caspase — P53 ↑,Bax↑, Mcl-1↓ [29]
HT-29 200 µM
IC50for= 78 µM — — [27]
Lime, parsley
Lime, parsley HeLa — — G1-phase
Hsp27arrest;
and3,7 P53
Hsp72 ↑ ↓,LC3
and
↑; Bcl2 ↓ P21 ↑; caspase
cleavage [30]
HT-29 and 5ICµM
50 =for
78 µM — imperatorin and
cisplatin 200 µM for — [27]
HeLa caspase 3,9 ↑; —3,7
cyt ↑; Bcl2 ↓↑; Bcl2 ↓,PARP
c release — Hsp27 and Hsp72 ↓,LC3 cleavage [30]
HL-60 10 5 µM
— for cisplatin — mTOR↓, p70S6K ↓, 4E-BP1↓, MAPK↓,
HCT116 150µM µM caspase 3,9 ↑; cyt c release ↑; Bcl2 ↓,PARP
cleavage
[28]
[31]
HL-60 10 µM — — HIF-1α inhibition [28]
H23 cleavage
P53 ↑,Bax↑, Mcl-1↓ mTOR↓, p70S6K ↓, 4E-BP1↓, MAPK↓,
HCT-15 = 10
IC50HCT116 19.4 µg/mL
± 0.3 µg·mL−1 —— —— [29]
H23 200 10
forµg/mL —150 µM — P53 ↑,Bax↑, Mcl-1↓ [29] HIF-1α inhibition
[31]
Imperatorin Lime, parsley A549
HeLa IC50µM = 16.4 imperatorin
± 0.3 µg·mL−1 —— —— Hsp27 and Hsp72 ↓,LC3 cleavage [30]
Imperatorin 200 µM
and 5=13.7
µM forforimperatorin
cisplatin
Lime, parsley HeLa
SK-OV-3 IC50HCT-15 ± 0.3 µg·mL−1 IC50 = 19.4— ± 0.3 µg·mL−1 — Hsp27 and↓— Hsp72 ↓,LC3 cleavage
cell viability —[30]
[23]
and 5 µM for cisplatin mTOR↓, p70S6K ↓, 4E-BP1↓, MAPK↓,
SK-MEL-2
HCT116 IC50 = 14.5 150 µM ± 0.2 µg·mL−1 — — [31]
mTOR↓, HIF-1α ↓, 4E-BP1↓, MAPK↓,
p70S6Kinhibition
HCT116
XF498 IC50 =A549 150± µM
12.3 0.5 µg·mL−1 IC50 = 16.4— ± 0.3 µg·mL —
−1 — —
[31]
HCT-15 IC50 = 19.4 ± 0.3 µg·mL−1 — — HIF-1α inhibition
HCT-15
A549 IC 50SK-OV-3
= 19.4 ±
IC50 = 16.4 ± 0.3 µg·mL 0.3 µg·mL−1−1 IC50 SGC-7901
=13.7
—— ± 0.3 µg·mL— −1
— — — ↓ cell viability [23]
Imperatorin cell-induced 10 mg/kg G1-phase arrest; caspase 3,9 ↑; Bax↑, Bcl2
Imperatorin A549
SGC-7901 IC50IC
50 =50 16.4
± ±0.3
= 18.75 0.3 µg·mL
µg·mL −1 −1 — — [32]
50 = 14.5
SK-OV-3 IC =13.7
SK-MEL-2 µg·mL −1 — model
ICxenograft ± 0.2 µg·mL −1
(20—days) ↓—cell viability
↓,Survivin↓ [23]
—
SK-OV-3
SK-MEL-2 ICIC 50 =13.7 ± 0.3 µg·mL−1
50 = 14.5 ± 0.2 µg·mL−1 —— —— ↓ cell viability [23]
(mice)
SK-MEL-2
XF498
DU145 ICIC5050==XF498
14.5±±0.5
12.3 0.2 µg·mL−1
100 µMµg·mL−1
IC50 = 12.3
——
—
± 0.5 µg·mL −1
——
—
—
G1-phase arrest
—
[33]
XF498 IC50 = 12.3 ± 0.5 µg·mL−1−1 —
SGC-7901 —
Lime, parsley HCT-15 IC50 = 5.6 ± 0.3 µg·mL — −1 — SGC-7901 cell-induced G1-phase arrest; caspase 3,9 ↑; Bax↑,
A549 (NSCLC) IC
SGC-7901 IC 50 = 18.75
SGC-7901
cell-induced µg·mL 10 mg/kg G1-phase arrest; caspase 10 mg/kg (20 days)
3,9 ↑; Bax↑, Bcl2 [32]
IC5050==12.2 ± 0.4 µg·mL — — xenograft model (mice) Bcl2 ↓, Survivin↓
−1
SGC-7901 18.75 µg·mL −1
cell-induced 10 days)
mg/kg G1-phase arrest; caspase 3,9 ↑; Bax↑, Bcl2 [32]
SGC-7901
SK-OV-3 ICIC5050= =6.8
18.75
± 0.3µg·mL
µg·mL−1 −1 xenograft—model (20 — ↓,Survivin↓ [32]
DU145 xenograft model
100 µM (20 days) ↓—↓,Survivin↓
cell viability [23]
— G1-phase arrest [33]
SK-MEL-2 IC50 = 9.9 ± 0.2 µg·mL−1 (mice)
— —
DU145 100 µM (mice)
— — G1-phase arrest [33]
XF498
DU145 HCT-15
IC50 = 10.7 ± µM 0.3 µg·mL−1 IC50 = 5.6— ± 0.3 µg·mL —
−1 — —
Isoimperatorin Lime, parsley HCT-15
Lime, parsley IC50 = 5.6100 ± 0.3 µg·mL−1 — — G1-phase arrest [33]
Lime, parsley
A549HCT-15 IC 50 = 5.6 ± 0.3 µg·mL−1
IC50 = 12.2— ± 0.4 µg·mL— —
−1 −1
(NSCLC) A549
IC 50 = 12.2 (NSCLC)
± 0.4 µg·mL — — —
A549 (NSCLC)
SK-OV-3 IC5050== 6.8
IC 12.2± ±0.3 0.4µg·mL
µg·mL −1
−1
—— ——
SK-OV-3 IC5050SK-OV-3 IC50 = 6.8 ± 0.3 µg·mL −1 ↓—cell viability —
[23] ↓ cell viability [23]
Broad bean, SK-MEL-2 IC ==9.96.8±±0.2 0.3µg·mL
µg·mL−1−1 —— ——
↓ cell viability [23]
SK-MEL-2 ICSK-MEL-2
50 = 9.9 ± 0.2 µg·mL−1 — 30mg/kg
— Bax↑, Bcl2 ↓,Bax/Bcl-2 ratio ↑;
blackberry, U937
XF498 IC50 = 10.7 IC50±=0.3 40 µM
µg·mL−1
IC50 =Mice
—
9.9 ± 0.2 µg·mL−1 — —
[34]
Isoimperatorin (30—days) G2/M-phase arrest
raspberry XF498 IC50 = 10.7 ± 0.3 µg·mL−1 — —
Isoimperatorin
Isoimperatorin
Marmesin XF498 IC50 = 10.7 ± 0.3 µg·mL −1 — —
Broad bean, Bax/Bcl-2 ↑, MMP2ratio↓,MMP9

Broad Broad
bean, bean, blackberry, 30mg/kg Bax↑, Bcl2ratio
↓,Bax/Bcl-2 ↑; Bax↑, Bcl2 ↓, Bax/Bcl-2 ratio ↑;
blackberry, U937
HepG2 IC 50 = 40 µM
U937100 µM 50 = 40 µM (30
Mice
IC— 30mg/kg
—
days) Bax↑,
↓,ERK1/2 Mice
Bcl2 ↓,Bax/Bcl-2
pathway
G2/M-phase ↑; c30mg/kg[34]
arrestratio cyt
inhibition, (30 days)
[35] [34]
blackberry, raspberry U937
raspberry IC50 = 40 µM Mice [34] G2/M-phase arrest
Anise, carrot, (30 days) G2/M-phase
release arrest
↑, AIF transposition ↑
Marmesin raspberry
Marmesin
Marmesin caraway celeriac,
celery, cumin, dill,
Methoxsalen/Xanthotoxin grapefruit, lemon, IC50 = 56.3 µM for Bax/Bcl-2 ratio ↑, MMP2 ↓,MMP9
SK-N-AS
HepG2 and 100 and
µM 88.5 µM — — Bax/Bcl-2
↓,ERK1/2 ratio ↑, MMP2
Caspase-3,8,9↑PI3K/AKT
pathway ↓,MMP9
pathway
inhibition, cyt↓,c Bcl2 [35]
(8-MOP) lime, parsley, SK-N-AS — — [36]
HepG2
SW620 100 µM — — ↓,ERK1/2
release↓,Bax/Bcl-2
pathway
↑, ratio ↑ ↑cyt c
inhibition,
AIF transposition [35]
Anise,
parsnip, carrot,
turnip for SW620
Anise,celeriac,
carrot, release ↑, AIF transposition ↑
caraway
caraway
celery, celeriac,
cumin, dill,
celery, cumin,
grapefruit, dill,
lemon, IC50 = 56.3 µM for
Methoxsalen/Xanthotoxin SK-N-AS and Caspase-3,8,9↑PI3K/AKT pathway ↓, Bcl2
Methoxsalen/Xanthotoxin grapefruit, lemon,
lime, parsley, IC50 = 56.3
SK-N-AS and µM
88.5for
µM — — [36]
(8-MOP) SK-N-AS
SW620 and Caspase-3,8,9↑PI3K/AKT pathway
↓,Bax/Bcl-2 ratio ↑ ↓, Bcl2
(8-MOP) lime, parsley,
parsnip, turnip SK-N-AS and 88.5 µM
for SW620 — — [36]
SW620 ↓,Bax/Bcl-2 ratio ↑
parsnip, turnip for SW620
cell-induced 10 mg/kg G1-phase arrest; caspase 3,9 ↑; Bax↑, Bcl2
SGC-7901 IC50 = 18.75 µg·mL−1 [32]
xenograft model (20 days) ↓,Survivin↓
(mice)
DU145 100 µM — — G1-phase arrest [33]
Lime, parsley HCT-15 IC50 = 5.6 ± 0.3 µg·mL−1 — —
A549 (NSCLC) IC50 = 12.2 ± 0.4 µg·mL−1 — —
SK-OV-3 IC50 = 6.8 ± 0.3 µg·mL−1 — —
↓ cell viability [23]
SK-MEL-2 IC50 = 9.9 ± 0.2 µg·mL−1 — —
Int. J. Mol. Sci. 2020, 21, 5622 6 of 20
XF498 IC50 = 10.7 ± 0.3 µg·mL−1 — —
Isoimperatorin
Broad bean, Table 1. Cont.

30mg/kg Bax↑, Bcl2 ↓,Bax/Bcl-2 ratio ↑;
blackberry, U937 IC50 = 40 µM Mice [34]
(30 days) G2/M-phase arrest
raspberry In Vitro In Vivo
Furanocoumarins
Marmesin Dietary Sources [2–4] Anticancer Mechanisms References
Cell Lines Cytotoxic Concentration Experimental Model Dose
Bax/Bcl-2 ratio ↑, MMP2 ↓,MMP9
Bax/Bcl-2 ratio ↑, MMP2 ↓, MMP9 ↓,
HepG2 100 µM — — ↓,ERK1/2 pathway inhibition, cyt c [35]
Anise, carrot, caraway HepG2 100 µM — — ERK1/2 pathway inhibition, cyt c [35]
Anise, carrot, celery, cumin, dill, release ↑, AIF transposition ↑
celeriac, release ↑, AIF transposition ↑
caraway celeriac,
grapefruit, lemon, lime,
celery, cumin, dill,
parsley, parsnip, turnip SK-N-AS and IC50 = 56.3 µM for SK-N-AS Caspase-3,8,9↑PI3K/AKT pathway ↓,
Methoxsalen/Xanthotoxin grapefruit, lemon, IC50 = 56.3 µM for — — [36]
Methoxsalen/Xanthotoxin (8-MOP)
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW SK-N-AS and SW620 and 88.5 µM8for SW620
of 22 Caspase-3,8,9↑PI3K/AKT pathway ↓, Bcl2 Bcl2 ↓, Bax/Bcl-2 ratio ↑
(8-MOP) lime, parsley, SK-N-AS and 88.5 µM — — [36]
SW620 ↓,Bax/Bcl-2 ratio ↑
parsnip, turnip L5178Yfor(mouse
SW620
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW L5178Y (mouse T-cell IC50 = 40.33 8±of0.63
22 µM — — caspase 3,9 ↑; cyt c release ↑; Bcl2 ↓ [37]
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW T-cell lymphoma lymphoma
IC50 = 40.33 cells)
± 0.63 µM — 8 of 22 — caspase 3,9 ↑; cyt c release ↑; Bcl2 ↓ [37]
L5178Ycells)
(mouse
HCT-15 IC50
HCT-15
= 40.33
3.4 ± 0.3 µg·mL −1
IC50 = 3.4
—
± 0.3 µg·mL−1— — —
L5178Y
T-cell (mouse
lymphoma IC 50 = ± 0.63 µM — — caspase 3,9 ↑; cyt c release ↑; Bcl2 ↓ [37]
Lime, parsley
Lime, parsley
A549cells)
T-cell (NSCLC)
lymphoma IC
IC5050 == 9.5
A549 ± 0.3
(NSCLC)
40.33 ± µg·mL −1
0.63 µM IC50 = 9.5
— ± 0.3 µg·mL−1
— —— caspase 3,9—↑; cyt c release ↑; Bcl2 ↓ —
[37]
SK-OV-3
cells)
HCT-15 IC
IC5050==19.3 3.4 ±±0.3
0.3µg·mL
µg·mL−1−1 —
— —
—
Lime, parsley SK-MEL-2
HCT-15 IC
SK-OV-3
IC505050===16.5
3.4 ±±±0.3
0.2µg·mL
µg·mL−1
−1
−1 IC50 = 19.3
—
—
± 0.3 µg·mL−1
—
—
— —
Oxypeucedanin A549 (NSCLC) IC 9.5 — —
Oxypeucedanin Lime, parsley
A549 XF498
(NSCLC)
SK-OV-3 IC
IC50
IC ==19.3
SK-MEL-2
5050= 16.1
9.5 ±±± 0.3
0.5 µg·mL
0.3 µg·mL−1
µg·mL −1
−1
IC50 = 16.5
— ± 0.2 µg·mL−1
—
— —
—
— — —
SK-OV-3
SK-MEL-2 IC5050 == 16.5
IC 19.3 ±± 0.2
0.3 µg·mL
µg·mL−1−1 —
— —
—
Oxypeucedanin
SK-MEL-2
XF498 IC5050 ==XF498
IC 16.5 ±± 0.5
16.1 0.2 µg·mL
µg·mL−1−1 IC50 = 16.1
—
−1
— ± 0.5 µg·mL —
— — —
Oxypeucedanin
XF498 IC50 = 16.1 ± 0.5 µg·mL−1 — — ↓ cell viability [23] ↓ cell viability [23]
A549, HCT-15,
Angelica dahurica ↓ cell viability [23]
SK-MEL-2, IC50 > 30 µg·mL−1 — —
roots ↓ cell viability [23]
SK-OV-3, XF498
A549, HCT-15,
Angelica dahurica A549, HCT-15,
AngelicaAngelica A549, HCT-15,
SK-MEL-2,
dahurica dahurica roots
roots
IC50 > 30 µg·mL−1
SK-MEL-2, > 30 µg·mL−1 —
IC50— — —
SK-MEL-2,
SK-OV-3, XF498 IC50 > 30XF498
SK-OV-3, µg·mL−1 — —
roots
SK-OV-3, XF498
(+)-oxypeucedanin hydrate
KBv200 75.3% (80 µg·mL−1) — — NF-κB inactivation G1/S phase arrest,
[38]
(+)-oxypeucedanin hydrate K562 92.4% (80 µg·mL−1) — — c-FLIP,and IAP inhibition
(+)-oxypeucedanin hydrate KBv200 17.32
75.3% (80± µg·mL
4.28% −1) — — NF-κB inactivation G1/S phase arrest,
MCF-7 — — G1/G0 phase arrest [39]
[38]
KBv200
K562 KBv200
(8 µg·mL
75.3%
92.4% (80
−1) −1
(80 µg·mL
µg·mL −1)
) 75.3%
——(80 µg·mL−1 ) —
— — IAP
NF-κBc-FLIP,and
inactivation G1/S phase arrest,
inhibition — NF-κB inactivation G1/S phase arrest,
Carrot, celeriac, [38] [38]
K562 92.4%
17.32(80 µg·mL−1)
± 4.28% — — G1 phase arrest, cyclin
c-FLIP,and E↓, Bax↑, Bcl2 ↓,
IAP inhibition
celery, cilantro, MCF-7 K562 −1 92.4% −1
—(80 µg·mL ) — —
G1/G0 phase arrest —
[39] c-FLIP, and IAP inhibition
17.32
(8 40 ±µM
µg·mL4.28%) ER stress, CHOP induction,
cumin, celeriac,
Carrot, dill, fig, SMMC7721
MCF-7 —— —
— G1/G0 phase arrest [40]
[39]
MCF-7
(8 µg·mL−1) −1
17.32 ± 4.28% (8 µg·mL ) GADD34↑,
— cyclinATF4↑,
G1 phase arrest, E↓, Bax↑, Bcl2 ↓, — G1/G0 phase arrest [39]
grapefruit, lemon,
Carrot,cilantro,
celery, celeriac,
G1 phase GRP78↑,
arrest,
ER stress, GRP94
cyclin
CHOP E↓, Bax↑, Bcl2 ↓,
induction,
Psoralen celery, Carrot,
lime,
cumin, dill, fig, celeriac,
parsley,
cilantro, celery,
SMMC7721 IC10 40= 8µM
µg/mL — — P-gp efflux function inhibition [40]
[41] G1 phase arrest, cyclin E↓, Bax↑, Bcl2 ↓,
parsnip ER stress, CHOP
GADD34↑, induction,
ATF4↑,
cumin,cilantro,
dill,
grapefruit, fig, cumin,SMMC7721
lemon, dill, fig, 40 µM — — [40] ER stress, CHOP induction,
IC50 = 25.59 ± 1.74
SMMC7721 40 µM GADD34↑,
GRP78↑, ATF4↑,
GRP94
— activity — [40]
lime, grapefruit,
grapefruit, lemon, lemon, lime,
parsley, P-gp ATPase inhibition
Psoralen MCF-7/ADR IC10 µg/mL
= 8 µg/mL GRP78↑,
P-gp efflux GRP94
function inhibition [41] GADD34↑, ATF4↑,
lime, parsley,
parsnipparsley, parsnip [42]
Psoralen
Psoralen ICIC =43.0
50 10 = 8 µM
µg/mL
25.59 ± 1.74 EMT inhibition
P-gp efflux function inhibition [41] GRP78↑, GRP94
parsnip P-gp ATPase activity inhibition
107.5
IC50 =µg/mL µM
25.59 ± 1.74 G0/G1 phase arrest
MCF-7/ADR IC10 = 8 µg/mL P-gp ATPase activity inhibition [42] P-gp efflux function inhibition [41]
MCF-7/ADR µg/mL
43.0 µM EMT inhibition
IC50 = 25.59 ± 1.74 µg/mL [42] P-gp ATPase activity inhibition
43.0
107.5 µM EMTphase
G0/G1 inhibition
arrest
MCF-7/ADR
107.5 µM G0/G1 phase arrest
Parsnip A549 50 µM 43.0 µM
— — NF-κB inactivation [43] EMT inhibition [42]
Sphondin Parsnip A549 50 µM — — NF-κB inactivation [43]
Parsnip A549 50 µM — — NF-κB inactivation [43]
Sphondin
Sphondin caspase-3,8↑; Bcl2 ↓; p38 MAPK
Lime SW480 25 µM (67%) — — phosphorylation inhibition; G1/G0 phase [44]
caspase-3,8↑;arrest
Bcl2 ↓; p38 MAPK
5-geranyloxy-7-methoxy-couma Lime SW480 25 µM (67%) — — phosphorylation Bcl2 ↓; p38G1/G0
caspase-3,8↑;inhibition; MAPK phase [44]
rin Lime SW480 25 µM (67%) — — phosphorylation inhibition;
arrest G1/G0 phase [44]
5-geranyloxy-7-methoxy-couma arrest
5-geranyloxy-7-methoxy-couma
rin
rin
roots
SK-OV-3, XF498
(+)-oxypeucedanin hydrate KBv200 75.3% (80 µg·mL−1) — — NF-κB inactivation G1/S phase arrest,
KBv200 75.3% (80 [38]
(80 µg·mL
µg·mL−1)) — —
−1
K562 92.4% — — NF-κBc-FLIP,and
inactivation G1/S
IAP phase arrest,
inhibition [38]
K562 92.4% (80
17.32 ± µg·mL
4.28% )
−1 — — c-FLIP,and IAP inhibition
MCF-7 17.32 ± 4.28% — — G1/G0 phase arrest [39]
Int. J. Mol. Sci. 2020, 21, 5622 MCF-7 (8 µg·mL −1)
— — G1/G0 phase arrest [39] 7 of 20
Carrot, celeriac, (8 µg·mL−1) G1 phase arrest, cyclin E↓, Bax↑, Bcl2 ↓,
Carrot, celeriac,
celery, cilantro, G1 phase arrest,CHOP
ER stress, cyclin E↓, Bax↑, Bcl2 ↓,
induction,
celery,
cumin, cilantro,
dill, fig, SMMC7721 40 µM — — [40]
ER stress, CHOPATF4↑,
GADD34↑, induction,
cumin, dill,
grapefruit, fig,
lemon, SMMC7721 40 µM — — [40]
GADD34↑, ATF4↑,
GRP78↑, GRP94
grapefruit, lemon,
lime, parsley, Table 1. Cont.
Psoralen IC10 = 8 µg/mL GRP78↑,
P-gp efflux GRP94
function inhibition [41]
Psoralen lime, parsley,
parsnip
parsnip ICIC = =25.59
50 10 8 µg/mL
± 1.74 P-gp efflux function inhibition [41]
IC50 =µg/mL
25.59 ± 1.74 P-gp ATPase activity inhibition
MCF-7/ADR In Vitro P-gp ATPase activityIn Vivo
inhibition
Furanocoumarins Dietary Sources [2–4]
MCF-7/ADR µg/mL [42] Anticancer Mechanisms References
43.0 µM EMT inhibition [42]
Cell43.0 Lines Cytotoxic Concentration Experimental Model Dose
107.5 µMµM EMT phase
G0/G1 inhibition
arrest
Parsnip Parsnip A549 50 µM

A549 —50 µM — NF-κB
— inactivation [43]
— NF-κB inactivation [43]
Parsnip A549 50 µM — — NF-κB inactivation [43]
Sphondin
Sphondin
Sphondin
caspase-3,8↑; Bcl2 ↓; p38 MAPK

Bcl2 ↓; p38G1/G0
caspase-3,8↑;inhibition; MAPKphase
caspase-3,8↑; Bcl2 ↓; p38 MAPK
Lime SW480 25 µM (67%) — — phosphorylation [44]
Lime Lime SW480 SW480
25 µM (67%) 25—µM (67%) — — inhibition; G1/G0 phase
phosphorylation —
[44] phosphorylation inhibition; G1/G0 [44]
arrest
5-geranyloxy-7-methoxy-couma arrest phase arrest
5-geranyloxy-7-methoxy-couma
rin
5-geranyloxy-7-methoxy-coumarin
rin
Human cancer cell lines: A549 (NSCLC), NCI-H460 (NSCLC), H23, and H1299 = lung cancer; Caki = renal carcinoma; DLD-1, LoVo, HCT-15, HT-29, HCT116, RKO, SW480 and
SW620 = colorectal cancer; DU145 = prostate cancer; HL-60 = promyelocytic leukemia; HeLa and SiHa = cervical cancer; HepG2, Huh-7 and SMMC7721 = liver carcinoma;
HT-1080 = fibrosarcoma; KBM-5, K562 = human chronic myeloid leukaemia; KBv200 = oral squamous carcinoma; MCF7 SKBR-3 and ZR-75 = breast cancer; SH-SY5Y and
SK-N-AS = neuroblastoma; SK-MEL-2 = melanoma; SK-OV-3 = ovarian cancer; SGC-7901 = gastric cancer cell; U937 = leukemia; U87 and U251 = glioma cells; XF498 = CNS solid tumor;
MCF-7/ADR = doxorubicin resistant derivatives of MCF-7 cells overexpressing P-gp; ↑ = increase; ↓ = decrease.
Int. J. Mol. Sci. 2020, 21, 5622 8 of 20
Figure 1. A schema of different molecular mechanisms that are targeted by furanocoumarin. It shows
Figure 1. A schema of different molecular mechanisms that are targeted by furanocoumarin. It shows
several molecular singling pathways modulation that leads to autophagy, apoptosis, angiogenesis,
several molecular singling
and metastasis. Black pathways
lines: induce,modulation that leads to autophagy, apoptosis, angiogenesis,
and red lines: inhibit.
and metastasis. Black lines: induce, and red lines: inhibit.
3. Bioavailability of Furocoumarins
Furanocoumarins are rapidly absorbed from food into the human bloodstream and detected
in plasma within 2–15 min after administration [20], and distributed to the skin, blood, liver, brain,
spleen, kidney, and testis. In plasma, furanocoumarins bind to albumins and other plasma proteins.
Furanocoumarins are metabolized to psoralen and isopsoralen by intestinal bacteria in the digestive
tract. Then, furanocoumarins are excreted into urine as hydroxylated or glucuronated products within
1 h after ingestion. They remain in urine as long as 24 h post-administration. It was also observed that
furanocoumarins are converted to bergaptol before excretion [11,21,22].
A significant advance in the investigation of the anticancer properties of furanocoumarins was the
revelation of their antiproliferative activity arresting cell-cycle capture and causing cell death [23–25].
At the cellular levels, furanocoumarins appear to affect actin filaments, which might be valuable in
metastasis prevention [26].
4. Mechanistic Insights
4.1. NF-κB Inactivation

NF-κB and STAT3 inactivation or inhibition cause apoptosis and consequent ineffectiveness of
anticancer treatments [23,24]. NF-κB and signal transducer and activator of transcription 3 (STAT3)
association triggers inflammation and cancer [25]. Bergamottin enhances tumor necrosis factor (TNF)
induced apoptosis in U87 and U251 via NF-κB and STAT3 inhibition [26]. The blocking of NF-κB
activity by psoralen (80 µg/mL) leads to inhibition of FADD like IL-1β converting enzyme inhibitory
protein (c-FLIP) and inhibitor of apoptosis proteins (IAP), activation of Bax, JNKs, and blocking G1/S
phase in KBv200 and K562 [27].
Int. J. Mol. Sci. 2020, 21, 5622 9 of 20
MMP-2,9 decrement, E-cadherin increment, EMT inhibition, and JNK cascade activation are
associated with NF-κB inactivation and result in antimetastatic behavior [28–32]. Angelicin inhibits
A549 non-small-cell lung carcinoma (NSCLC) growth and metastasis by reducing MMP-2,9; increasing
E-cadherin expression levels and JNK, and ERK activation [33]. Bergamottin inhibited the migration
abilities of A549, H1299 [34]; HT-1080 cells [35] and human fibrosarcoma HT-1080 cells [36],
by decreasing the phorbol 12-myristate 13-acetate (PMA)-initiated enactment of matrix metallo
proteinase (MMP)-2,9; c-jun N-terminal kinase (JNK) phosphorylation and EMT inhibition through
NF-κB inactivation. Psoralen give similar response in MCF-7/ADR cells [37]. Rac1 blocks drug-induced
apoptosis by maintaining Bad in the phosphorylated state [38]. Inactivation of Rac 1 is also responsible
for NF-κB inactivation [39]. Bergamottin exhibits antimetastatic behavior in U87 and U251 human
glioma cells through Rac1 inactivation and MMP-9 downregulation [26].
In chronic inflammation, immune cells generate excessive ROS and RNS in the inflamed tissue and
reinforce the NF-κB mediated inflammatory responses that can lead to tumorigenesis. Therefore, NF-κB
down regulation is helpful in cancer prevention and treatment by exerting anti-inflammatory effect [40,41].
NF-κB expresses cytokines, chemokines, and also maintains the inflammatory response through
persistent leukocyte activation [42,43]. Sphondin inhibits IL-1β-initiated-COX-2 by NF-κB inactivation
in the A549 cell line [44]. Imperatorin reduced IL-6, -1β, and TNF-α discharge and inhibited iNOS
and COX-2 by repressing NF-κB in RAW 264.7 (murine-macrophages-cell lines) [45,46]. Bergamottin,
Bergapten and Psoralen inhibit ROS/NO generation for anti-inflammatory activity [35,47,48].
4.2. PI3K/Akt Inhibition

Activated PI3K/Akt contributes to (i) protection of cells from apoptosis, by inactivation of Bax, Bad,
Bak, Bid, MDM2, caspase-9, and Bax and causes activation of cyclic AMP responsive element binding
protein (CREB) to induce transcription of Bcl-2, (ii) regulation of cell metabolism; (iii) fatty acid synthesis.
In apoptosis, cytosol Bax releases caspase-activating Cyt-c. The caspase-8 (extrinsic apoptosis) or -9
(intrinsic apoptosis), is activated which further activates caspase-3, essential to propagates apoptotic
signal [49–53]. Cell shrinkage and chromatin condensation helps in apoptosis [54]. Activated caspase-3
stimulates inhibitor of caspase activated DNAse (ICAD) to release caspase-activated DNAse (CAD),
which condenses the chromatin [55]. Angelicin in PC-3 cells [56] and bergamottin in A549 (NSCLC) cell
lines [57] cause chromatin condensation. Imperatorin induced selective antitumor effects in SGC-7901
cells without causing too much cytotoxicity to the normal mouse fibroblast cells (3T3 cells). It also
induced apoptosis, G1 phase arrest, DNA fragmentation, and downregulation of PI3K/Akt/m-TOR
signaling pathway [58]. Methoxsalen (8-MOP) activated caspase-8 -9, Bax/Bcl-2 ratio upregulation,
cytochrome-c (Cyt-c) release, and CREB phosphorylation decrement to down-regulates Bcl-2 for
apoptosis in SW620 and SK-N-AS cells, through PI3K/Akt down-regulation [51]. Angelicin increases
Bax, caspase-3, -9, decreases Bcl-2, Bcl-xL, Mcl-1 in A549 (NSCLC) cells [33], and SH-SY5Y cells [59]
to induce intrinsic mitochondria-mediated apoptosis. Angelicin, and in combination, activated
caspase-3 and decreased FADD like IL-1β converting enzyme inhibitory protein (c-FLIP) in Caki
(renal carcinoma) cells to induce apoptosis [60]. Bergamottin induces apoptosis in human colon
carcinoma cell line (RKO) and HT-29 cells by increasing caspase-3, 8, and 9; and PARP cleavage [61].
Bergapten inhibits breast cancer cell line (MCF-7) growth [62] and CRC cell viability [63] via inhibition
of Akt. Bergaptol inducesMCF-7 cytotoxicity by the same mechanism [64]. Methoxsalen (8-MOP)
inducesHepG2 cells apoptosis by Bax/Bcl-2 increment, MMPs decrement, and Cyt-c release and AIF
transposition induction [65]. Imperatorinin duce’s both intrinsic and extrinsic apoptotic pathways
by Bcl-2 protein expression downregulation, caspase-3, -7, -8, -9 activation, releases mitochondrial
Cyt-c to the cytosol and cleaves poly (ADP-ribose) polymerase (PARP) in HT-29, HL-60 [52,66],
SNU 449, HCT-15 [67], and HepG2 cells [68]. Isoimperatorin induces the apoptosis in SGC-7901 and
in vivo xenograft model by Bax, caspase-3, -9 increment, and Survivin and Bcl-2 decrement in nude
mice [69]. Marmesin inhibits colony formation and induces apoptosis in U937 cells by triggering
Bax upregulation, Bcl-2 downregulation, and Bax/Bcl-2 ratio increment [70]. Byakangelicol, cnidicin,
Int. J. Mol. Sci. 2020, 21, 5622 10 of 20
imperatorin, isoimperatorin, oxypeucedanin and (+)-oxypeucedanin hydrate from Angelica dahurica

roots exert cytotoxicity in A549, HCT-15, SK-OV-3, SK-MEL-2, XF498 cells by similar mechanisms [71].
5-geranyloxy-7-methoxycoumarin from lime suppressesSW480 cell proliferation by apoptosis through
caspase-3, -8 activation, regulation of Bcl2, and p38 MAPK phosphorylation inhibition [72]. Psoralen
causes Bax increment and attenuates Bcl-2 expression in SMMC7721 human hepatoma cells [73]. Liver X
receptor (LXR) regulates lipid metabolism, inflammation and induces apoptosis through caspase-3
activation [74]. LXRs activation increases ABCA1 cholesterol transporters and inducible degrader
of the low-density lipoprotein receptor (IDOL) in turn triggering low-density lipoprotein receptor
(LDLR) degradation and reducing intracellular cholesterol, thereby reducing SREBPs, tumor growth,
and survival. Highly expressed SREBPs play important roles in malignancies, connecting oncogenic
signaling to lipid metabolism alterations, leading to rapid tumor growth. PI3K-Akt pathway is
inhibited by LXRs [53,75]. Bergapten inhibits liver carcinogenesis (HepG2) by activating LXRs,
inhibiting PI3K/Akt that reduced SREBP-1, fatty acid synthase (FASN), stearoyl-CoA desaturase-1
(SCD1), thereby preventing fatty acid synthesis and tumor growth [53].
The antitumor effects of angelicin involves decreased expression of p-VEGFR2 and PI3K/Akt
signaling inhibition in HepG2 and Huh-7 cells. In the same study, angelicin was shown to decrease
p-VEGFR in mouse liver orthotopic xenograft model [17]. Bergamottin suppresses TGF-β initiated
EMT and the cell invasive potential by PI3K, Akt, and mTOR kinases [35].
4.3. p53 Modulation

The p53 controls cell cycle progression and regulates apoptosis and autophagy [76]. p53 activation
promotes p21 and p27 expression, which restrain cyclin E and Cdk2 activity, thereby cause cell cycle
phase arrest [77]. Bergapten increases p53 activity that induces p21 transcription, which, in turn,
inhibits G2/M phase in HepG2 cells [11]; triggers G1 arrest in A549, NCI H460 [78] and MCF-7 cells [62].
p53 protein intervenes in two major apoptotic pathways: an “extrinsic pathway” induced by death
receptors (TNF proteins such as DR4 and DR5) and an “intrinsic pathway” that regulates Family
Bcl-2 proteins [5]. Bergapten (30 and 50 µM) decreased CRC (colorectal cancer) cells’ viability by
apoptosis via upregulation of p53, p21, and PTEN [63]. Furanocoumarin A from Fructus liquidambaris
induces the apoptosis in A549 by increasing p53 [79]. Imperatorin significantly upregulates p53 and
p21, which subsequently results in Mcl-1 down-regulation and Bax up-regulation in H23 human lung
cancer cell [80] and HT 29 colon cancer cells [52] to inhibit their growth. Psoralen upregulates p21,
waf and p53 in cells SKBR-3 MCF-7 cells, causing apoptosis [81,82]. Similarly, 5-geranyloxy-7-methoxy
coumarin induces apoptosis in SW480 cells through the activation of tumor suppressor gene p53 [72].
Psoralen inhibits SMMC7721 cells (human hepatoma cell line) proliferation by ER stress induction
by apoptosis. During ER-stress, glucose regulatory protein 78 (GRP78), GRP94, protein kinase R-like
ER kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor-6 (ATF6),
growth arrest and DNA damage inducible protein 34 (GADD34), and ATF4 increment can promote C/E
B P homologous protein (CHOP) and high expression of CHOP, thereby inhibiting Bcl-2 and promoting
apoptosis [73].
Psoralen causes exosomes formation and secretion reduction through p53 and PPAR activation in
MCF-7/ADR cells, which showed its role against chemotherapy resistance in breast cancer [83].
The antioxidant functions of p53 protein also induces apoptosis and autophagy [5,84]. Imperatorin
increases p53, in turn, exerting antioxidant effects that may contribute to its anticancer effects [85,86].
4.4. Cell Cycle Arrest

Cell cycle progression or arrest is related to cyclin-A, -B1, -D1, -E1 and cyclin B1, cyclin E1,
Cdc2, Cdk2 and Wnt/β-catenin [87–89]. Angelicin suppresses proliferation of A549 cells; HeLa and
SiHa cells by promoting G2/M and G1/G0 phase arrest respectively by cyclin-B1, -E1 and Cdc2
downregulation [33,90].Bergamottin arrests HT-29, RKO and A549 (NSCLC) cells at G2/M by cyclin-A,
-B1 and Cdc2 depletion [57,61]. Bergapten (5-MOP) blocks G2/M phase in Hep-G2 with the inhibition
Int. J. Mol. Sci. 2020, 21, 5622 11 of 20
of Cdk1 [91]. Bergapten (30 and 50 µM) instigated the G0/G1 and sub-G1 stage capture in CRC cells
by a decrease of cyclin E/Cdk2 [63]. Bergaptol arrests G1-phase in MCF-7 [64]; Imperatorin in HT 29
and SGC-7901 cells [52,58] and isoimperatorin in DU145 and SGC-790 cells by increasing Cip1/p21
and Kip1/p27 expression and disrupting Cdk4 kinase synthesis [69,92]. Marmesin captures G2/M and
cell migration in U937 [70]. Psoralen arrests at G1 phase in SMMC7721 by Cyclin-E1 reduction [73].
Psoralen arrests G0/G1 by deregulation of Wnt/β-catenin in MCF-7 [93].
4.5. Autophagy
Increase in autophagy results in cell growth inhibition and apoptosis [94,95]. Angelicin accumulated
microtubule-associated LC3B and upregulated Atg-3,7 and 12-5 in HeLa and SiHa cells [90]. PTEN is
downregulated to corneal tumors [96]. Bergapten exhibited autophagy in MCF-7 and ZR-75 by PTEN,
AMBRA, Beclin1, PI3KIII and, UVRAG up-regulation and LC3-II conversion [97]. Feroniellin-A from
Feroniella lucida roots initiates autophagy in A549 by LC3-II conversion; Beclin-1 and Atg-5 enhanced
expression [98].
4.6. Antioxidant
Oxidative stress is caused by ROS accumulation and high ROS concentration is demanded
by cancerous cells. Anticancer phytochemicals with antioxidants properties reduce developing
cancer risks [45,99]. Bergamottin, bergaptol, methoxsalen [100], bergapten [101], imperatorin [102],
oxypeucedanin [103] and psoralen [104] have been reported to possess antioxidant activities.
N-nitrosodiethylamine (NDEA) causes oxidative stress and responsible for the carcinogenic effect.
Bergapten has shown to possess anticancer potential in vivo against NDEA-induced liver cancer via
antioxidant effects [53]. Hypoxia is a noteworthy component of tumor malignant growth, and it activates
hypoxia inducible factor (HIF), thus increasing tumor survival and proliferation [85]. Antioxidants
inhibit HIF-1 α activity by scavenging free radicals [105]. Imperatorin has been shown to inhibitHIF-1
in HCT116 due to its antioxidant behavior and mTOR/p70S6K/4E-BP1 and MAPK downregulation [86].
5. Role in MDR Cancers

Cancer cell defiance to chemotherapy is one of the significant deterrents for counter cancer
medications due to the involvement of different mechanisms. The main causes are related to the
increment of multidrug efflux pumps, including P-gp by tumor cells, and showed MDR. Coumarins
have a significant role in MDR inversion [106–108].
Psoralen inverts the P-gp-instigated MDR in MCF-7/ADR by repressing the efflux capacity of P
gp [108] and by hindrance of P-gp ATPase activity [37]. Similarly, isopimpinellin (IC50 value 26 µM)
and Phellopterin (IC50 value 8 µM) exhibited cytotoxic activity against MDR HL-60/MX2 (human
promyelocytic leukemia cells) and CEM/C1 (human lymphoblastic leukemia cells) respectively [109].
Feroniellin A reduces MDR in A549 cell lines by decreasing P-gp [98]. MDR1rapidly pumps out
anticancer drugs, decreases intracellular drug concentrations and leads to the failure of anticancer
therapeutics [110]. Similarly, BCRP and MRP overexpression participates in MDR [111,112]. Bergapten
and methoxsalen showed cytotoxicity in MDR1, MRP2 BCRP overexpressing gastric (EPG85.257RDB),
ovarian (A2780RCIS) and breast (MCF7MX) cancer cell lines which showed reticence of MDR1, BCRP,
and MRP efflux functions [113].
ETRα positive and estrogen dependence are seen in 70% of breast cancers. ETRα depletion during
initial stages of breast cancer is a potent anticancer approach [114]. Xanthotoxol, bergapten, angelicin,
psoralen and isoimperatorin antagonized ETRα activity in MCF-7 cells with IC50 values of 0.72, 1.18,
11.02, 24.08 and 54.32 µM, respectively [115].
Exosomes, secreted from tumor cells to promote tumor progression, such as metastasis and MDR,
activate sequestration of anticancer drugs by MDR-1 and P-gp [116]. Psoralen significantly reduces
the number of exosomes, which correlates with increased MCF-7/ADR cells’ sensitivity for apoptosis
Int. J. Mol. Sci. 2020, 21, 5622 12 of 20
under the influence of chemotherapy. Similar observations were seen in A 549/D16 lung cancer cell
lines [11,83,117].
6. Furanocoumarins as Adjuvant with Other Anticancer Agents

Invasion and angiogenesis are important targets of FC (Figure 2). In a study, given that bergamottin
(50 µM)-potentiated simvastatin (SV) inhibits TNF-induced NF-κB activation and IκBα deterioration,
cell-cycle capture in S-phase by boost of p21 and p27 in KBM-5 cells. This impact of co-treatment is
associated with decrease incyclin D1 (cell proliferation), Bcl-2, cIAP-1, Bcl-xL and survivin (cell survival),
MMP-9 (invasion), and VEGF (angiogenesis) which are directed by NF-κB. CYP P450 34A inhibition
by bergamottin enhances SV bioavailability in KBM-5 to synergize SV effects [35,118].Cytochrome
P450 upregulation in cancer makes it one of the effective strategy against it. CYP P450 inhibition
by furanocoumarins and other phytoconstituents leads to anticarcinogenic effects, down regulating
MDR and prolonging the t1/2 of other anticancer drugs [119,120]. Bergamottin, DHBG, bergapten,
and bergaptol inhibit CYP P450 34A to potentiate vinblastine effects [121]. Bergamottin, imperatorin,
and isopimpinellin repressed CYP P450-1A1, -1A2, -3A4, and -1B1 (involve in carcinogen metabolism),
in the MCF-7 cell lines [122]. MDR has been linked to BCRP, MRP, and MDR1 increase that expel
cisplatin, daunorubicin, and mitoxantrone are very common in cancer therapeutics [113]. Bergapten
and methoxsalen are capable of averting mitoxantrone, cisplatin, and daunorubicin binding to MDR1,
BCRP, and MRP and, therefore, impeding their cellular efflux [113]. Bergamottin, DHBG, bergapten,
and bergaptol from grapefruit juice inhibit P-gp and MRP2 mediated vinblastine efflux [121]. Long-term
use of tamoxifen in breast cancer leads to MDR and an increased risk of endometrial carcinogenesis [123].
Bergapten degrades and depletes ETRα from MCF-7 tamoxifen-resistant cells by inducing SMAD4
protein to block mitogenic signals [62]. The anticancer effects of doxorubicin in HeLa cells are enhanced
by Imperatorin via Mcl-1 down-regulation [124]. Imperatorin (100 µM) effectively increasing autophagy
in HeLa cells in response to cisplatin (2 µM) by microtubule-associated protein 1A/1B-light chain 3
(LC3) cleavage
Int. J. Mol.and the21,inhibition
Sci. 2020, of Hsp27 and Hsp72 [125]. Imperatorin potentiates the
x FOR PEER REVIEW cytotoxicity
14 of 22
of cisplatin in hepatocellular carcinoma (HCC) cells (HepG2, HepG3B, PLC, Huh7) by downregulating
potentiates the cytotoxicity of cisplatin in hepatocellular carcinoma (HCC) cells (HepG2, HepG3B,
Mcl-1 expression [126].
PLC, Huh7) by downregulating Mcl-1 expression [126].
Figure 2. A schema of anti-angiogenesis effects of furanocoumarin. FC via activation/inhibition of a

Figure 2. A schema of anti-angiogenesis effects of furanocoumarin. FC via activation/inhibition of a
sequences of cellular and molecular pathways exerts its anti-angiogenesis effects. Black lines: induce,
sequences of cellular and molecular pathways exerts its anti-angiogenesis effects. Black lines: induce,
7. Furanocoumarins and Cancer Risks
PUVA therapy (photoactivated psoralens) is beneficial for patients with vitiligo, psoriasis, and
skin diseases. PUVA activates caspase-3, -8 and -9 in Jurkat (human tumor T-cell line) [127].PUVA,
the photoactivated psoralens (5-MOP and 8-MOP) induce apoptosis in MCF-7, ZR-75 and SKBR-3 by
caspase and p53 upregulation, PI3K/AKT downregulation and effective against breast
Int. J. Mol. Sci. 2020, 21, 5622 13 of 20
7. Furanocoumarins and Cancer Risks

PUVA therapy (photoactivated psoralens) is beneficial for patients with vitiligo, psoriasis,
and skin diseases. PUVA activates caspase-3, -8 and -9 in Jurkat (human tumor T-cell line) [127].
PUVA, the photoactivated psoralens (5-MOP and 8-MOP) induce apoptosis in MCF-7, ZR-75 and
SKBR-3 by caspase and p53 upregulation, PI3K/AKT downregulation and effective against breast
hormone-responsive cancers [128]. PUVA arrest G2/M phase by phospho-Chk1 increment and
phospho-Cdc2 decrement in B16F10 murine melanoma cell line [129]. Unfortunately, it is linked toa
risk of basal cell, squamous cell, and non-melanoma skin cancers [130,131]. PUVA has been approved
by the FD, [132]. PUVA is ideal for superficial applications only, due to low penetration into deep
tissues. Therefore, X-PACT has been introduced, which at low X-ray doses photoactivates psoralens
and hence mitigates the low penetration problem and adverse effects of PUVA [133].
8. Conclusions
Chemotherapy and radiation are the staples for treatment of malignant growth, however, both have
serious adverse health symptoms. It is known that tumors have developed many mechanisms at the
molecular level enabling cell survival during chemotherapy. Therefore, it is essential to develop novel
pharmaceuticals with increased efficacy and reduced toxicity. This review highlights the potential
for furanocoumarins to be clinically beneficial in cancer, particularly given their specificity to tumor
cells (while sparing normal cells). In vitro investigations have shown that furanocoumarins affect a
range of cellular mechanisms, such as apoptosis, autophagy, and cell cycle arrest. ER stress induction
mainly caused by NF-κB inactivation, PI3K/Akt inhibition, and p53 modulation. Furanocoumarins
are also effective in different MDR cancers that are the main cause of anticancer therapeutics failure.
Compounds in this class have also have been shown to positively synergize with commonly used
anticancer drugs. The fast absorption of furanocoumarins from food into the human bloodstream is also
noteworthy [134]. Furanocoumarins, by inhibiting CYP P450 3A4, not only have anticancer properties
but also when co-administered with a low bioavailability anticancer compound can increase oral
bioavailability [135]. Thus, as to improve genuine treatments for various sorts of tumors, nanomedicine
has developed new strategies coordinated to build the efficacy of medications focusing on tumors and
limit their side effects [136,137]. Furanocoumarin-loaded lipid-polymer-hybrid-nanoparticles represent
an additional option for sustained release of these molecules to improve efficacy and synergistic effects
with other anticancer agents and against MDR cancers [108,138,139]. To date, most focus has been on
in vitro studies, making it hard to reach solid conclusions on the efficacy of furanocoumarins in vivo.
Nonetheless, studies aimed at characterizing furanocoumarin’s efficacy in vivo as well as clinical
studies are encouraging, supporting the need for future studies to better characterize furanocoumarin’s
potential as efficacious anticancer treatment modalities.
Author Contributions: Conceptualization, H.K. and M.A.; drafting the manuscript, S.A., H.K., M.A., H.M., and
E.K.A.; review and editing the paper: H.K., M.A., and R.C.; revising S.A., H.K., M.A., H.M., E.K.A, and R.C. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Singh, S.; Sharma, B.; Kanwar, S.S.; Kumar, A. Lead phytochemicals for anticancer drug development.
Front. Plant Sci. 2016, 7, 1667. [CrossRef] [PubMed]
2. Ashraf, M.A. Phytochemicals as potential anticancer drugs: Time to Ponder Nature’s Bounty. BioMed Res. Int.
2020, 2020, 8602879. [CrossRef]
3. Khattak, S.; Khan, H. Anti-cancer potential of phyto-alkaloids: A prospective review. Curr. Cancer Ther. Rev.
2016, 12, 66–75. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 5622 14 of 20
4. Rauf, A.; Khan, R.; Khan, H.; Tokuda, H. Cytotoxic, antitumor-promoting and inhibition of protein denaturation
effects of flavonoids, isolated from Potentilla evestita Th. Wolf. Nat. Prod. Res. 2015, 29, 1775–1778. [CrossRef]
5. Khan, H.; Reale, M.; Ullah, H.; Sureda, A.; Tejada, S.; Wang, Y.; Zhang, Z.-J.; Xiao, J. Anti-cancer effects of
polyphenols via targeting p53 signaling pathway: Updates and future directions. Biotechnol. Adv. 2020,
38, 107385. [CrossRef] [PubMed]
6. Spector, D. Optimizing Cancer Survivors’ Health: The Role of Lifestyle Behaviors. J. Nurse Pract. 2018, 14, 323–329.
[CrossRef]
7. Patridge, E.V.; Gareiss, P.; Kinch, M.; Hoyer, D. An analysis of FDA-approved drugs: Natural products and
their derivatives. Drug Discov. Today 2016, 21, 204–207. [CrossRef]
8. Faraone, I.; Sinisgalli, C.; Ostuni, A.; Armentano, M.F.; Carmosino, M.; Milella, L.; Russo, D.; Labanca, F.;
Khan, H. Astaxanthin anticancer effects are mediated through multiple molecular mechanisms: A systematic
review. Pharmacol. Res. 2020, 155, 104689. [CrossRef]
9. Del Río, J.A.; Diaz, L.; García-Bernal, D.; Blanquer, M.; Ortuño, A.; Correal, E.; Moraleda, J.M.
Furanocoumarins: Biomolecules of therapeutic interest. In Studies in Natural Products Chemistry; Rahman, A.,
Ed.; Elsevier: Amsterdam, The Netherlands, 2014; Volume 43, pp. 145–195.
10. Melough, M.M.; Cho, E.; Chun, O.K. Furocoumarins: A review of biochemical activities, dietary sources and
intake, and potential health risks. Food Chem. Toxicol. 2018, 113, 99–107. [CrossRef] [PubMed]
11. Sumorek-Wiadro, J.; Zajac, ˛ A.; Maciejczyk, A.; Jakubowicz-Gil, J.; Joanna, S.-W.; Adrian, Z.; Aleksandra, M.;
Joanna, J.-G. Furanocoumarins in anticancer therapy-For and against. Fitoterapia 2020, 142, 104492. [CrossRef]
[PubMed]
12. Olomola, T.O.; Mosebi, S.; Klein, R.; Traut-Johnstone, T.; Coates, J.; Hewer, R.; Kaye, P.T. Novel furocoumarins
as potential HIV-1 integrase inhibitors. Bioorg. Chem. 2014, 57, 1–4. [CrossRef] [PubMed]
13. Pynam, H.; Dharmesh, S.M. Antioxidant and anti-inflammatory properties of marmelosin from Bael
(Aegle marmelos L.); Inhibition of TNF-α mediated inflammatory/tumor markers. Biomed. Pharmacother. 2018,
106, 98–108. [CrossRef] [PubMed]
14. Melis, C.; Distinto, S.; Bianco, G.; Meleddu, R.; Cottiglia, F.; Fois, B.; Taverna, D.; Angius, R.; Alcaro, S.;
Ortuso, F.; et al. Targeting Tumor Associated Carbonic Anhydrases IX and XII: Highly Isozyme Selective
Coumarin and Psoralen Inhibitors. ACS Med. Chem. Lett. 2018, 9, 725–729. [CrossRef] [PubMed]
15. Niu, C.; Lu, X.; Aisa, H.A. Preparation of novel 1,2,3-triazole furocoumarin derivatives via click chemistry
and their anti-vitiligo activity. RSC Adv. 2019, 9, 1671–1678. [CrossRef]
16. Niu, C.; Yin, L.; Aisa, H.A. Novel Furocoumarin Derivatives Stimulate Melanogenesis in B16 Melanoma
Cells by Up-Regulation of MITF and TYR Family via Akt/GSK3β/β-Catenin Signaling Pathways. Int. J.
Mol. Sci. 2018, 19, 746. [CrossRef]
17. Wang, F.; Li, J.; Li, R.; Pan, G.; Bai, M.; Huang, Q. Angelicin inhibits liver cancer growth in vitro and in vivo.
Mol. Med. Rep. 2017, 16, 5441–5449. [CrossRef]
18. Guillon, C.; Jan, Y.-H.; Foster, N.; Ressner, J.; Heck, D.E.; Laskin, J.D.; Heindel, N.D. Synthetically modified
methoxsalen for enhanced cytotoxicity in light and dark reactions. Bioorg. Med. Chem. Lett. 2019, 29, 619–622.
[CrossRef]
19. Carbone, A.; Montalbano, A.; Spanò, V.; Musante, I.; Galietta, L.J.; Barraja, P. Furocoumarins as multi-target
agents in the treatment of cystic fibrosis. Eur. J. Med. Chem. 2019, 180, 283–290. [CrossRef]
20. Fujioka, T.; Furumi, K.; Fujii, H.; Okabe, H.; Mihashi, K.; Nakano, Y.; Matsunaga, H.; Katano, M.; Mori, M.
Antiproliferative constituents from Umbelliferae plants. V. A new furanocoumarin and falcarindiol
furanocoumarin ethers from the root of Angelica japonica. Chem. Pharm. Bull. 1999, 47, 96–100. [CrossRef]
21. Gawron, A.; Glowniak, K. Cytostatic activity of coumarins in vitro. Planta Med. 1987, 53, 526–529. [CrossRef]
22. Widelski, J.; Kukula-Koch, W.; Baj, T.; Kedzierski, B.; Fokialakis, N.; Magiatis, P.; Pozarowski, P.; Roliński, J.;
Graikou, K.; Chinou, I. Rare Coumarins Induce Apoptosis, G1 Cell Block and Reduce RNA Content in HL60
Cells. Open Chem. 2017, 15, 1–6. [CrossRef]
23. Godwin, P.; Baird, A.-M.; Heavey, S.; Barr, M.; O’Byrne, K.J.; Gately, K.A. Targeting Nuclear Factor-Kappa B
to Overcome Resistance to Chemotherapy. Front. Oncol. 2013, 3, 120. [CrossRef] [PubMed]
24. Aoki, Y.; Feldman, G.M.; Tosato, G. Inhibition of STAT3 signaling induces apoptosis and decreases survivin
expression in primary effusion lymphoma. Blood 2003, 101, 1535–1542. [CrossRef] [PubMed]
25. Dong, Z.; Bode, A.M.; Dong, Z. Breaking the NF-κB and STAT3 alliance inhibits inflammation and pancreatic
tumorigenesis. Cancer Prev. Res. 2010, 3, 1379–1381. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 5622 15 of 20
26. Luo, W.; Song, Z.; Sun, H.; Liang, J.; Zhao, S. Bergamottin, a natural furanocoumarin abundantly present
in grapefruit juice, suppresses the invasiveness of human glioma cells via inactivation of Rac1 signaling.
Oncol. Lett. 2018, 15, 3259–3266. [CrossRef]
27. Wang, Y.; Hong, C.; Zhou, C.; Xu, D.; Qu, H.-B. Screening antitumor compounds psoralen and isopsoralen
from Psoralea corylifolia L. seeds. Evid.-Based Complement. Altern. Med. 2011, 2011, 363052. [CrossRef]
28. Augustin, S.; Berard, M.; Kellaf, S.; Peyri, N.; Fauvel-Lafève, F.; Legrand, C.; He, L.; Crépin, M. Matrix
metalloproteinases are involved in both type I (apoptosis) and type II (autophagy) cell death induced by
sodium phenylacetate in MDA-MB-231 breast tumour cells. Anticancer Res. 2009, 29, 1335–1343.
29. Chase, A.J.; Bond, M.; Crook, M.F.; Newby, A. Role of nuclear factor-kappa B activation in metalloproteinase-1,
-3, and -9 secretion by human macrophages in vitro and rabbit foam cells produced in vivo. Arter. Thromb.
Vasc. Biol. 2002, 22, 765–771. [CrossRef]
30. Artacho-Cordón, F.; Ríos-Arrabal, S.; Lara, P.; Artacho-Cordón, A.; Calvente, I.; Nuñez, M. Matrix
metalloproteinases: Potential therapy to prevent the development of second malignancies after breast
radiotherapy. Surg. Oncol. 2012, 21, e143–e151. [CrossRef]
31. Escárcega, R.O.; Fuentes-Alexandro, S.; García-Carrasco, M.; Gatica, A.; Zamora, A. The Transcription Factor
Nuclear Factor-kappa B and Cancer. Clin. Oncol. 2007, 19, 154–161. [CrossRef]
32. Papa, S.; Zazzeroni, F.; Pham, C.G.; Bubici, C.; Franzoso, G. Linking JNK signaling to NF-B: A key to survival.
J. Cell Sci. 2004, 117, 5197–5208. [CrossRef] [PubMed]
33. Li, G.; Song, X.; He, Y.; Yao, J.; Huang, C.; Deng, Y.; Xie, S.; Ren, J.; Jin, M.; Liu, H. Angelicin inhibits human
lung carcinoma A549 cell growth and migration through regulating JNK and ERK pathways. Oncol. Rep.
2016, 36, 3504–3512. [CrossRef] [PubMed]
34. Ko, J.H.; Nam, D.; Um, J.Y.; Jung, S.H.; Sethi, G.; Ahn, K.S. Bergamottin Suppresses Metastasis of Lung
Cancer Cells through Abrogation of Diverse Oncogenic Signaling Cascades and Epithelial-to-Mesenchymal
Transition. Molecules (Basel, Switzerland) 2018, 23, 1601. [CrossRef] [PubMed]
35. Ko, J.-H.; Arfuso, F.; Sethi, G.; Ahn, K.S. Pharmacological Utilization of Bergamottin, Derived from Grapefruits,
in Cancer Prevention and Therapy. Int. J. Mol. Sci. 2018, 19, 4048. [CrossRef]
36. Hwang, Y.P.; Yun, H.J.; Choi, J.H.; Kang, K.W.; Jeong, H.G. Suppression of phorbol-12-myristate-13-
acetate-induced tumor cell invasion by bergamottin via the inhibition of protein kinase Cδ/p38
mitogen-activated protein kinase and JNK/nuclear factor-κB-dependent matrix metalloproteinase-9
expression. Mol. Nutr. Food Res. 2009, 54, 977–990. [CrossRef]
37. Wang, X.; Cheng, K.; Han, Y.; Zhang, G.; Dong, J.; Cui, Y.; Yang, Z. Effects of psoralen as an anti-tumor agent
in human breast cancer MCF-7/ADR cells. Biol. Pharm. Bull. 2016, 39, 815–822. [CrossRef]
38. Embade, N.; Valerón, P.F.; Aznar, S.; López-Collazo, E.; Lacal, J.C. Apoptosis Induced by Rac GTPase
Correlates with Induction of FasL and Ceramides Production. Mol. Biol. Cell 2000, 11, 4347–4358. [CrossRef]
39. Gastonguay, A.; Berg, T.; Hauser, A.D.; Schuld, N.; Lorimer, E.; Williams, C.L. The role of Rac1 in the
regulation of NF-kappaB activity, cell proliferation, and cell migration in non-small cell lung carcinoma.
Cancer Biol. Ther 2012, 13, 647–656. [CrossRef]
40. Rayburn, E.R.; Ezell, S.J.; Zhang, R. Anti-Inflammatory Agents for Cancer Therapy. Mol. Cell. Pharmacol.
2009, 1, 29–43. [CrossRef]
41. Khan, H.; Ullah, H.; Castilho, P.C.M.F.; Gomila, A.S.; D’Onofrio, G.; Filosa, R.; Wang, F.; Nabavi, S.M.;
Daglia, M.; Silva, A.S.; et al. Targeting NF-kappaB signaling pathway in cancer by dietary polyphenols. Crit.
Rev. Food Sci. Nutr. 2019, 12, 1–11. [CrossRef]
42. Lawrence, T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009,
1, a001651. [CrossRef] [PubMed]
43. Ahmed, S.; Khan, H.; Fratantonio, D.; Hasan, M.M.; Sharifi, S.; Fathi, N.; Ullah, H.; Rastrelli, L.; Sharifi, S.
Apoptosis induced by luteolin in breast cancer: Mechanistic and therapeutic perspectives. Phytomedicine
2019, 59, 152883. [CrossRef] [PubMed]
44. Yang, L.-L.; Liang, Y.C.; Chang, C.W.; Lee, W.-S.; Kuo, C.T.; Wang, C.C.; Lee, H.-M.; Lin, C.-H. Effects of
sphondin, isolated from Heracleum laciniatum, on IL-1beta-induced cyclooxygenase-2 expression in human
pulmonary epithelial cells. Life Sci. 2002, 72, 199–213. [CrossRef]
45. Nasser, M.; Zhu, S.; Hu, H.; Huang, H.; Guo, M.; Zhu, P. Effects of imperatorin in the cardiovascular system
and cancer. Biomed. Pharmacother. 2019, 120, 109401. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 5622 16 of 20
46. Zhang, X.; Li, W.; Abudureheman, A.; Cheng, T.; Peng, P. Imperatorin possesses notable anti-inflammatory
activity in vitro and in vivo through inhibition of the NF kappa B pathway. Mol. Med. Rep. 2017, 16, 8619–8626.
[CrossRef]
47. Yang, Y.; Zheng, K.; Mei, W.; Wang, Y.; Yu, C.; Yu, B.; Deng, S.; Hu, J. Anti-inflammatory and pro resolution
activities of bergapten isolated from the roots of Ficus hirta in an in vivo zebrafish model. Biochem. Biophys.
Res. Commun. 2018, 496, 763–769. [CrossRef]
48. Li, X.; Yu, C.; Hu, Y.; Xia, X.; Liao, Y.; Zhang, J.; Chen, H.; Lu, W.; Zhou, W.; Song, Z. New application
of psoralen and angelicin on periodontitis with anti-bacterial, anti-inflammatory, and osteogenesis effects.
Front. Microbiol. 2018, 8, 178. [CrossRef]
49. A West, K.; Castillo, S.S.; Dennis, P.A. Activation of the PI3K/Akt pathway and chemotherapeutic resistance.
Drug Resist. Updat. 2002, 5, 234–248. [CrossRef]
50. Nicholson, K.M.; Anderson, N.G. The protein kinase B/Akt signalling pathway in human malignancy.
Cell Signal 2002, 14, 381–395. [CrossRef]
51. Bartnik, M.; Sławińska-Brych, A.; Żurek, A.; Kandefer-Szerszeń, M.; Zdzisińska, B. 8-methoxypsoralen
reduces AKT phosphorylation, induces intrinsic and extrinsic apoptotic pathways, and suppresses cell
growth of SK-N-AS neuroblastoma and SW620 metastatic colon cancer cells. J. Ethnopharmacol. 2017,
207, 19–29. [CrossRef]
52. Zheng, Y.M.; Lu, A.X.; Shen, Z.; Kwok, A.H.Y.; Ho, W.S. Imperatorin exhibits anticancer activities in human
colon cancer cells via the caspase cascade. Oncol. Rep. 2016, 35, 1995–2002. [CrossRef] [PubMed]
53. Pattanayak, S.P.; Bose, P.; Sunita, P.; Siddique, M.U.M.; Lapenna, A. Bergapten inhibits liver carcinogenesis by
modulating LXR/PI3K/Akt and IDOL/LDLR pathways. Biomed. Pharmacother. 2018, 108, 297–308. [CrossRef]
[PubMed]
54. Toné, S.; Sugimoto, K.; Tanda, K.; Suda, T.; Uehira, K.; Kanouchi, H.; Samejima, K.; Minatogawa, Y.;
Earnshaw, W.C. Three distinct stages of apoptotic nuclear condensation revealed by time-lapse imaging,
biochemical and electron microscopy analysis of cell-free apoptosis. Exp. Cell Res. 2007, 313, 3635–3644.
[CrossRef] [PubMed]
55. Elmore, S.A. Apoptosis: A Review of Programmed Cell Death. Toxicol. Pathol. 2007, 35, 495–516. [CrossRef]
[PubMed]
56. Wang, Q.; Wang, Y.-P.; Lin, H.; Zhang, L.-Q.; Wu, L.-J.; Pang, L.-X. Antiproliferative and apoptotic effects of
angelicin in highly invasive prostate cancer cells. Trop. J. Pharm. Res. 2015, 14, 1405–1411. [CrossRef]
57. Wu, H.-J.; Wu, H.-B.; Zhao, Y.-Q.; Chen, L.-J.; Zou, H.-Z. Bergamottin isolated from Citrus bergamia exerts
in vitro and in vivo antitumor activity in lung adenocarcinoma through the induction of apoptosis, cell cycle
arrest, mitochondrial membrane potential loss and inhibition of cell migration and invasion. Oncol. Rep.
2016, 36, 324–332. [CrossRef] [PubMed]
58. Am, J.U.; Gong, W.J.; Su, Y.; Mou, Z.B. Imperatorin shows selective antitumor effects in SGC-7901 human
gastric adenocarcinoma cells by inducing apoptosis, cell cycle arrest and targeting PI3K/Akt/m-TOR signalling
pathway. J. Balk. Union Oncol. 2018, 22, 1471–1476.
59. Ataur Rahman, M.; Kim, N.-H.; Yang, H.; Huh, S.-O. Angelicin induces apoptosis through intrinsic
caspase-dependent pathway in human SH-SY5Y neuroblastoma cells. Mol. Cell. Biochem. 2012, 369, 95–104.
[CrossRef]
60. Min, K.J.; Um, H.J.; Seo, S.U.; Woo, S.M.; Kim, S.; Park, J.W.; Lee, H.S.; Kim, S.H.; Choi, Y.H.; Lee, T.J.
Angelicin potentiates TRAIL-induced apoptosis in renal carcinoma Caki cells through activation of caspase 3
and down-regulation of c-FLIP expression. Drug Dev. Res. 2017, 79, 3–10. [CrossRef]
61. Zhang, H.; Yang, S.; Lin, T. Bergamottin exerts anticancer effects on human colon cancer cells via induction
of apoptosis, G2/M cell cycle arrest and deactivation of the Ras/Raf/ERK signalling pathway. Arch. Med. Sci.
2019, 15. [CrossRef]
62. Panno, M.L.; Giordano, F.; Rizza, P.; Pellegrino, M.; Zito, D.; Giordano, C.; Mauro, L.; Catalano, S.; Aquila, S.;
Sisci, D. Bergapten induces ER depletion in breast cancer cells through SMAD4-mediated ubiquitination.
Breast Cancer Res. Treat. 2012, 136, 443–455. [CrossRef] [PubMed]
63. Lin, C.P.; Lin, C.S.; Lin, H.H.; Li, K.T.; Kao, S.H.; Tsao, S.M. Bergapten induces G1 arrest and pro-apoptotic
cascade in colorectal cancer cells associating with p53/p21/PTEN axis. Environ. Toxicol. 2019, 34, 303–311.
[CrossRef] [PubMed]
Int. J. Mol. Sci. 2020, 21, 5622 17 of 20
64. Ge, Z.-C.; Qu, X.; Yu, H.-F.; Zhang, H.-M.; Wang, Z.-H.; Zhang, Z.-T. Antitumor and apoptotic effects of
bergaptol are mediated via mitochondrial death pathway and cell cycle arrest in human breast carcinoma
cells. Bangladesh J. Pharmacol. 2016, 11, 489–494. [CrossRef]
65. Yang, H.; Xiong, J.; Luo, W.; Jian, Y.; Xi, T. 8-Methoxypsoralen Induces Intrinsic Apoptosis in HepG2 Cells:
Involvement of Reactive Oxygen Species Generation and ERK1/2 Pathway Inhibition. Cell. Physiol. Biochem.
2015, 37, 361–374. [CrossRef] [PubMed]
66. Pae, H.-O.; Oh, H.; Yun, Y.-G.; Oh, G.-S.; Jang, S.I.; Hwang, K.-M.; Kwon, T.-O.; Lee, H.-S.; Chung, H.-T.
Imperatorin, a furanocoumarin from Angelica dahurica (Umbelliferae), induces cytochrome c-dependent
apoptosis in human pro myelocytic leukaemia, HL-60 Cells. Pharmacol. Toxicol. 2002, 91, 40–48. [CrossRef]
67. Rahman, A.; Siddiqui, S.A.; Jakhar, R.; Kang, S.C. Growth inhibition of various human cancer cell lines by
imperatorin and limonin from Poncirus trifoliata Rafin. Seeds. Anticancer Agents Med. Chem. 2015, 15, 236–241.
[CrossRef]
68. Luo, K.-W.; Sun, J.-G.; Chan, J.; Yang, L.; Wu, S.; Fung, K.-P.; Liu, F. Anticancer Effects of Imperatorin
Isolated from Angelica dahurica: Induction of Apoptosis in HepG2 Cells through both Death-Receptor- and
Mitochondria-Mediated Pathways. Chemotherapy 2011, 57, 449–459. [CrossRef]
69. Tong, K.; Xin, C.; Chen, W. Isoimperatorin induces apoptosis of the SGC-7901 human gastric cancer cell line
via the mitochondria-mediated pathway. Oncol. Lett. 2016, 13, 518–524. [CrossRef]
70. Dong, L.; Xu, W.-W.; Li, H.; Bi, K.-H. In vitro and in vivo anticancer effects of marmesin in U937 human
leukemia cells are mediated via mitochondrial-mediated apoptosis, cell cycle arrest, and inhibition of cancer
cell migration. Oncol. Rep. 2017, 39, 597–602. [CrossRef]
71. Kim, Y.-K.; Ryu, S.Y. Antiproliferative Effect of Furanocoumarins from the Root of Angelica dahurica on
Cultured Human Tumor Cell Lines. Phytother. Res. 2007, 21, 288–290. [CrossRef]
72. Patil, J.; Jayaprakasha, G.K.; Kim, J.; Murthy, K.; Chetti, M.; Nam, S.-Y.; Patil, B.S. 5-Geranyloxy-7-
Methoxycoumarin inhibits colon cancer (SW480) cells growth by inducing apoptosis. Planta Med. 2013,
73. Wang, X.; Peng, P.; Pan, Z.; Fang, Z.; Lu, W.; Liu, X. Psoralen inhibits malignant proliferation and induces
apoptosis through triggering endoplasmic reticulum stress in human SMMC7721 hepatoma cells. Biol. Res.
2019, 52, 34. [CrossRef] [PubMed]
74. Zhang, W.; Jiang, H.; Zhang, J.; Zhang, Y.; Liu, A.; Zhao, Y.; Zhu, X.; Lin, Z.; Yuan, X. Liver X receptor
activation induces apoptosis of melanoma cell through caspase pathway. Cancer Cell Int. 2014, 14, 16.
[CrossRef] [PubMed]
75. Cheng, X.; Li, J.; Guo, D. SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets
in Cancer Therapy. Curr. Top. Med. Chem. 2018, 18, 484–493. [CrossRef] [PubMed]
76. Karimian, A.; Ahmadi, Y.; Yousefi, B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional
regulation after DNA damage. DNA Repair 2016, 42, 63–71. [CrossRef] [PubMed]
77. Harris, S.L.; Levine, A.J. The p53 pathway: Positive and negative feedback loops. Oncogene 2005, 24, 2899–2908.
[CrossRef]
78. Chiang, S.; Lin, C.; Lin, H.; Shieh, P.; Kao, S.-H. Bergapten induces G1 arrest of non-small cell lung cancer
cells, associated with the p53-mediated cascade. Mol. Med. Rep. 2019, 19, 1972–1978. [CrossRef]
79. Fang, H.; Ji, H. Furanocoumarin A: A Novel Anticancer agent on human lung cancer A549 cells from Fructus
liquidambaris. Anticancer Agents Med. Chem. 2019, 19, 2091–2096. [CrossRef]
80. Choochuay, K.; Chunhacha, P.; Pongrakhananon, V.; Luechapudiporn, R.; Chanvorachote, P. Imperatorin
sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells. J. Nat. Med. 2012, 67, 599–606.
[CrossRef]
81. Panno, M.L.; Giordano, F. Effects of psoralens as anti-tumoral agents in breast cancer cells. World J. Clin. Oncol.
2014, 5, 348–358. [CrossRef]
82. Panno, M.L.; Giordano, F.; Palma, M.G.; Bartella, V.; Rago, V.; Maggiolini, M.; Sisci, D.; Lanzino, M.;
De Amicis, F.; Ando, S. Evidence that bergapten, independently of its photoactivation, enhances p53 gene
expression and induces apoptosis in human breast cancer cells. Curr. Cancer Drug Targets 2009, 9, 469–481.
[CrossRef] [PubMed]
83. Wang, X.; Xu, C.; Hua, Y.; Sun, L.; Cheng, K.; Jia, Z.; Han, Y.; Dong, J.; Cui, Y.; Yang, Z. Exosomes play
an important role in the process of psoralen reverse multidrug resistance of breast cancer. J. Exp. Clin.
Cancer Res. 2016, 35, 186. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2020, 21, 5622 18 of 20
84. Simabuco, F.M.; Morale, M.G.; Pavan, I.C.; Morelli, A.P.; Silva, F.R.; Tamura, R.E. p53 and metabolism:
From mechanism to therapeutics. Oncotarget 2018, 9, 23780–23823. [CrossRef] [PubMed]
85. Burroughs, S.K.; Kaluz, S.; Wang, D.; Wang, K.; Van Meir, E.G.; Wang, B. Hypoxia inducible factor pathway
inhibitors as anticancer therapeutics. Future Med. Chem. 2013, 5, 553–572. [CrossRef]
86. Mi, C.; Ma, J.; Wang, K.S.; Zuo, H.X.; Wang, Z.; Li, M.Y.; Piao, L.-X.; Xu, G.-H.; Li, X.; Quan, Z.-S.
Imperatorin suppresses proliferation and angiogenesis of human colon cancer cell by targeting HIF-1α via
the mTOR/p70S6K/4E-BP1 and MAPK pathways. J. Ethnopharmacol. 2017, 203, 27–38. [CrossRef]
87. Haseeb, M.; Pirzada, R.H.; Ain, Q.U.; Choi, S. Wnt Signaling in the Regulation of Immune Cell and Cancer
Therapeutics. Cells 2019, 8, 1380. [CrossRef]
88. Ingham, M.; Schwartz, G.K. Cell-Cycle Therapeutics Come of Age. J. Clin. Oncol. 2017, 35, 2949–2959.
[CrossRef]
89. Mills, C.C.; Kolb, E.; Sampson, V.B. Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer.
Cancer Res. 2017, 77, 6489–6498. [CrossRef]
90. Wang, Y.; Chen, Y.; Chen, X.; Liang, Y.; Yang, D.; Dong, J.; Yang, N.; Liang, Z. Angelicin inhibits the malignant
behaviors of human cervical cancer potentially via inhibiting autophagy. Exp. Ther. Med. 2019, 18, 3365–3374.
[CrossRef]
91. Lee, Y.; Wu, T.; Chen, S.; Chung, J.-G. Effect of 5-methoxypsoralen (5-MOP) on cell apoptosis and cell cycle in
human hepatocellular carcinoma cell line. Toxicol. In Vitro 2003, 17, 279–287. [CrossRef]
92. Kang, J.-H.; Lee, S.-K.; Yim, D.-S. Effect of isoimperatorin on the proliferation of prostate cancer cell line
DU145 cells. Biomol. Ther. 2005, 13, 185–189.
93. Wang, X.; Xu, C.; Hua, Y.; Cheng, K.; Zhang, Y.; Liu, J.; Han, Y.; Liu, S.; Zhang, G.; Xu, S.; et al. Psoralen
induced cell cycle arrest by modulating Wnt/β-catenin pathway in breast cancer cells. Sci. Rep. 2018, 8, 14001.
[CrossRef] [PubMed]
94. Chen, N.; Karantza, V. Autophagy as a therapeutic target in cancer. Cancer Biol. Ther. 2011, 11, 157–168.
[CrossRef] [PubMed]
95. Yun, C.W.; Lee, S.H. The Roles of Autophagy in Cancer. Int. J. Mol. Sci. 2018, 19, 3466. [CrossRef]
96. Song, M.S.; Salmena, L.; Pandolfi, P.P. The functions and regulation of the PTEN tumour suppressor. Nat. Rev.
Mol. Cell Biol. 2012, 13, 283–296. [CrossRef]
97. De Amicis, F.; Aquila, S.; Morelli, C.; Guido, C.; Santoro, M.; Perrotta, I.; Mauro, L.; Giordano, F.; Nigro, A.;
Andò, S.; et al. Bergapten drives autophagy through the up-regulation of PTEN expression in breast cancer
cells. Mol. Cancer 2015, 14, 130. [CrossRef]
98. Kaewpiboon, C.; Surapinit, S.; Malilas, W.; Moon, J.; Phuwapraisirisan, P.; Tip-Pyang, S.; Johnston, R.N.;
Koh, S.S.; Assavalapsakul, W.; Chung, Y.-H. Feroniellin A-induced autophagy causes apoptosis in
multidrug-resistant human A549 lung cancer cells. Int. J. Oncol. 2014, 44, 1233–1242. [CrossRef]
99. Haq, S.H.; Al-Ruwaished, G.; Al-Mutlaq, M.A.; Naji, S.A.; Al-Mogren, M.; Al-Rashed, S.; Ain, Q.T.;
Al-Amro, A.A.; Al-Mussallam, A. Antioxidant, anticancer activity and phytochemical analysis of Green
Algae, Chaetomorpha collected from the Arabian Gulf. Sci. Rep. 2019, 9, 1–7. [CrossRef]
100. Hung, W.-L.; Suh, J.H.; Wang, Y. Chemistry and health effects of furanocoumarins in grapefruit. J. Food
Drug Anal. 2017, 25, 71–83. [CrossRef]
101. Karakaya, S.; Koca, M.; Yılmaz, S.V.; Yıldırım, K.; Pınar, N.M.; Demirci, B.; Brestic, M.; Sytar, O. Molecular
docking studies of coumarins isolated from extracts and essential oils of Zosima absinthifolia Link as potential
inhibitors for Alzheimer’s Disease. Molecules 2019, 24, 722. [CrossRef]
102. Cao, Y.; Zhang, Y.; Wang, N.; He, L. Antioxidant effect of imperatorin from Angelica dahurica in hypertension
via inhibiting NADPH oxidase activation and MAPK pathway. J. Am. Soc. Hypertens. 2014, 8, 527–536.
[CrossRef] [PubMed]
103. Razavi, S.; Zahri, S.; Motamed, Z.; Ghasemi, G. Bioscreening of oxypeucedanin, a known Furanocoumarin.
Iran J. Basic. Med. Sci. 2010, 13, 133–138.
104. Dhalwal, K.; Shinde, V.M.; Namdeo, A.G.; Mahadik, K.R. Antioxidant profile and HPTLC-Densitometric
analysis of umbelliferone and psoralen in Aegle marmelos. Pharm. Biol. 2008, 46, 266–272. [CrossRef]
105. Upadhyay, J.; Kesharwani, R.K.; Misra, K. Comparative study of antioxidants as cancer preventives through
inhibition of HIF-1 alpha activity. Bioinformation 2009, 4, 233–236. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 5622 19 of 20
106. Kasaian, J.; Mosaffa, F.; Behravan, J.; Masullo, M.; Piacente, S.; Ghandadi, M.; Iranshahi, M. Reversal
of P-glycoprotein-mediated multidrug resistance in MCF-7/Adr cancer cells by Sesquiterpene coumarins.
Fitoterapia 2015, 103, 149–154. [CrossRef]
107. Dewanjee, S.; Dua, T.K.; Bhattacharjee, N.; Das, A.; Gangopadhyay, M.; Khanra, R.; Joardar, S.; Riaz, M.;
De Feo, V.; Zia-Ul-Haq, M. Natural products as alternative choices for P-Glycoprotein (P-gp) inhibition.
Molecules 2017, 22, 871. [CrossRef]
108. Jiang, J.; Wang, X.; Cheng, K.; Zhao, W.; Hua, Y.; Xu, C.; Yang, Z. Psoralen reverses the P-glycoprotein-mediated
multidrug resistance in human breast cancer MCF-7/ADR cells. Mol. Med. Rep. 2016, 13, 4745–4750. [CrossRef]
109. Kubrak, T.; Bogucka-Kocka, A.; Komsta, Ł.; Załuski, D.; Bogucki, J.; Galkowski, D.; Kaczmarczyk, R.;
Feldo, M.; Adamczyk-Cioch, M.; Kocki, J. Modulation of multidrug resistance gene expression by coumarin
derivatives in human leukemic cells. Oxid. Med. Cell. Longev. 2017, 2017, 1–13. [CrossRef]
110. Fletcher, J.I.; Haber, M.; Henderson, M.J.; Norris, M.D. ABC transporters in cancer: More than just drug
efflux pumps. Nat. Rev. Cancer 2010, 10, 147–156. [CrossRef]
111. Nakanishi, T.; Ross, U.D. Breast cancer resistance protein (BCRP/ABCG2): Its role in multidrug resistance
and regulation of its gene expression. Chin. J. Cancer 2012, 31, 73–99. [CrossRef]
112. Deng, L.; Tatebe, S.; Lin-Lee, Y.-C.; Ishikawa, T.; Kuo, M.T. MDR and MRP Gene Families as Cellular Determinant
Factors for Resistance to Clinical Anticancer Agents; Springer Science and Business Media LLC: Berlin/Heidelberg,
Germany, 2002; Volume 112, pp. 49–66.
113. Mirzaei, S.A.; Dehkordi, N.G.; Ghamghami, M.; Amiri, A.; Abdolahinia, E.D.; Elahian, F. ABC-transporter
blockage mediated by xanthotoxin and bergapten is the major pathway for chemo sensitization of
multidrug-resistant cancer cells. Toxicol. Appl. Pharmacol. 2017, 337, 22–29. [CrossRef] [PubMed]
114. Sui, M.; Huang, Y.; Park, B.H.; Davidson, N.E.; Fan, W. Estrogen receptor α mediates breast cancer cell
resistance to paclitaxel through inhibition of apoptotic cell death. Cancer Res. 2007, 67, 5337–5344. [CrossRef]
[PubMed]
115. Acharya, R.; Chacko, S.; Bose, P.; Lapenna, A.; Pattanayak, S.P. Structure Based Multitargeted Molecular
docking analysis of selected furanocoumarins against breast cancer. Sci. Rep. 2019, 9, 1–13. [CrossRef]
116. Yousafzai, N.A.; Wang, H.; Wang, Z.; Zhu, Y.; Zhu, L.; Jin, H.; Wang, X. Exosome mediated multidrug
resistance in cancer. Am. J. Cancer Res. 2018, 8, 2210–2226.
117. Hsieh, M.J.; Chen, M.K.; Yu, Y.Y.; Sheu, G.T.; Chiou, H.L. Psoralen reverses docetaxel-induced multidrug
resistance in A549/D16 human lung cancer cells lines. Phytomedicine 2014, 21, 970–977. [CrossRef] [PubMed]
118. Kim, S.M.; Lee, E.J.; Lee, J.H.; Yang, W.M.; Nam, D.; Lee, J.H.; Lee, S.G.; Um, J.Y.; Shim, B.S.; Ahn, K.S.
Simvastatin in combination with bergamottin potentiates TNF-induced apoptosis through modulation of
NF-κB signalling pathway in human chronic myelogenous leukemia. Pharm. Biol. 2016, 54, 2050–2060.
[CrossRef]
119. Alzahrani, A.M.; Rajendran, P. The Multifarious Link between Cytochrome P450s and Cancer. Oxid. Med.
Cell. Longev. 2020, 2020, 3028387. [CrossRef] [PubMed]
120. Lin, S.; Chang, C.; Hsu, C.; Tsai, M.; Cheng, H.; Leong, M.K.; Sung, P.; Chen, J.; Weng, C. Natural compounds
as potential adjuvants to cancer therapy: Preclinical evidence. Br. J. Pharmacol. 2019, 177, 1409–1423.
[CrossRef]
121. Ohnishi, A.; Matsuo, H.; Yamada, S.; Takanaga, H.; Morimoto, S.; Shoyama, Y.; Ohtani, H.; Sawada, Y.
Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on
the activity of cytochrome P450 3A4. Br. J. Pharmacol. 2000, 130, 1369–1377. [CrossRef]
122. Kleiner, H.E.; Reed, M.J.; DiGiovanni, J. Naturally Occurring Coumarins Inhibit Human Cytochromes P450
and Block Benzo[a]pyrene and 7,12-Dimethylbenz[a]anthracene DNA Adduct Formation in MCF-7 Cells.
Chem. Res. Toxicol. 2003, 16, 415–422. [CrossRef]
123. Herynk, M.H.; Fuqua, S.A. Estrogen receptors in resistance to hormone therapy. Retin. Degener. Dis. 2007,
608, 130–143. [CrossRef]
124. Zheng, Y.; Jiang, K. Antitumor effect of imperatorin enhances cytotoxicity of doxorubicin to HeLa cells.
Chin. J. Pathophysiol. 2015, 31, 1578–1583.
125. Jakubowicz-Gil, J.; Paduch, R.; Ulz, Z.; Badziul, D.; Głowniak, K.; Gawron, A. Cell death in HeLa cells upon
imperatorin and cisplatin treatment. Folia Histochem. Cytobiol. 2012, 50, 381–391. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 5622 20 of 20
126. Hu, J.; Xu, C.; Cheng, B.; Jin, L.; Li, J.; Gong, Y.; Lin, W.; Pan, Z.; Pan, C.-W. Imperatorin acts as a cisplatin
sensitizer via downregulating Mcl-1 expression in HCC chemotherapy. Tumor Biol. 2015, 37, 331–339.
[CrossRef]
127. Viola, G.; Fortunato, E.; Cecconet, L.; Disarò, S.; Basso, G. Induction of apoptosis in Jurkat cells by photoexcited
psoralen derivatives: Implication of mitochondrial dysfunctions and caspases activation. Toxicol. In Vitro
2007, 21, 211–216. [CrossRef] [PubMed]
128. Panno, M.L.; Giordano, F.; Mastroianni, F.; Palma, M.G.; Bartella, V.; Carpino, A.; Aquila, S.; Andò, S. Breast
cancer cell survival signal is affected by bergapten combined with an ultraviolet irradiation. FEBS Lett. 2010,
129. Sumiyoshi, M.; Sakanaka, M.; Taniguchi, M.; Baba, K.; Kimura, Y. Anti-tumor effects of various furocoumarins
isolated from the roots, seeds and fruits of Angelica and Cnidium species under ultraviolet A irradiation.
J. Nat. Med. 2013, 68, 83–94. [CrossRef] [PubMed]
130. Stern, R.S. The risk of squamous cell and basal cell cancer associated with psoralen and ultraviolet A therapy:
A 30-year prospective study. J. Am. Acad. Dermatol. 2012, 66, 553–562. [CrossRef] [PubMed]
131. Dowdy, J.C.; Sayre, R.M. Melanoma risk from dietary furocoumarins: How much more evidence is required?
J. Clin. Oncol. 2016, 34, 636–637. [CrossRef] [PubMed]
132. DelRosso, G.; Savoia, P. Effectiveness and Safety of Topical Phototherapy in the Treatment of Dermatological
Diseases. Photomed. Adv. Clin. Pract. 2017, 137–151. [CrossRef]
133. Oldham, M.; Yoon, S.W.; Fathi, Z.; Beyer, W.F.; Adamson, J.; Liu, L.; Alcorta, D.; Xia, W.; Osada, T.; Liu, C.; et al.
X-Ray Psoralen Activated Cancer Therapy (X-PACT). PLoS ONE 2016, 11, e0162078. [CrossRef] [PubMed]
134. Melough, M.M.; Chun, O.K. Dietary furocoumarins and skin cancer: A review of current biological evidence.
Food Chem. Toxicol. 2018, 122, 163–171. [CrossRef] [PubMed]
135. He, K.; Hollenberg, P.F.; Woolf, T.F. Compositions Containing Bergamottin for Increasing the Oral
Bioavailability of Pharmaceutical Agents. U.S. Patent No. 6,509,371B1, 21 June 2003.
136. Brigger, I.; Dubernet, C.; Couvreur, P.; Patrick, C. Nanoparticles in cancer therapy and diagnosis. Adv. Drug
Deliv. Rev. 2012, 64, 24–36. [CrossRef]
137. Bor, G.; Azmi, I.D.M.; Yaghmur, A. Nanomedicines for cancer therapy: Current status, challenges and future
prospects. Ther. Deliv. 2019, 10, 113–132. [CrossRef] [PubMed]
138. Huang, Q.; Cai, T.; Li, Q.; Huang, Y.; Liu, Q.; Wang, B.; Xia, X.; Wang, Q.; Whitney, J.C.C.; Cole, S.P.C.; et al.
Preparation of psoralen polymer-lipid hybrid nanoparticles and their reversal of multidrug resistance in
MCF-7/ADR cells. Drug Deliv. 2018, 25, 1056–1066. [CrossRef] [PubMed]
139. Mottaghipisheh, J.; Nové, M.; Spengler, G.; Kúsz, N.; Hohmann, J.; Csupor, D. Antiproliferative and cytotoxic
activities of furocoumarins of Ducrosia anethifolia. Pharm. Biol. 2018, 56, 658–664. [CrossRef]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Aspiritin

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Aspiritin

Uploaded by

Copyright:

Available Formats

International Journal of

Keywords: furanocoumarin; apoptosis; autophagy; metastasis; cell cycle arrest

Int. J. Mol. Sci. 2020, 21, 5622; doi:10.3390/ijms21165622 www.mdpi.com/journal/ijms

HepG2 50 mM — — PI3K/AKT inhibition, LXR (α and β)↑

SK-OV-3 IC50 = 20.2 ± 0.3 µg·mL−1 — —

XF498 IC50 = 28.4 ± 0.3 µg·mL−1 — —

Broad bean, Bax/Bcl-2 ↑, MMP2ratio↓,MMP9

Broad bean, Table 1. Cont.

Parsnip Parsnip A549 50 µM

caspase-3,8↑; Bcl2 ↓; p38 MAPK

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 22

4.1. NF-κB Inactivation

4.2. PI3K/Akt Inhibition

imperatorin, isoimperatorin, oxypeucedanin and (+)-oxypeucedanin hydrate from Angelica dahurica

4.3. p53 Modulation

4.4. Cell Cycle Arrest

5. Role in MDR Cancers

6. Furanocoumarins as Adjuvant with Other Anticancer Agents

Figure 2. A schema of anti-angiogenesis effects of furanocoumarin. FC via activation/inhibition of a

7. Furanocoumarins and Cancer Risks

You might also like