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Bitter Melon (Momordica Charantia), a Nutraceutical Approach for Cancer Prevention and Therapy

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Abstract and Figures

Cancer is the second leading cause of death worldwide. Many dietary plant products show promising anticancer effects. Bitter melon or bitter gourd (Momordica charantia) is a nutrient-rich medicinal plant cultivated in tropical and subtropical regions of many countries. Traditionally, bitter melon is used as a folk medicine and contains many bioactive components including triterpenoids, triterpene glycoside, phenolic acids, flavonoids, lectins, sterols and proteins that show potential anticancer activity without significant side effects. The preventive and therapeutic effects of crude extract or isolated components are studied in cell line-based models and animal models of multiple types of cancer. In the present review, we summarize recent progress in testing the cancer preventive and therapeutic activity of bitter melon with a focus on underlying molecular mechanisms. The crude extract and its components prevent many types of cancers by enhancing reactive oxygen species generation; inhibiting cancer cell cycle, cell signaling, cancer stem cells, glucose and lipid metabolism, invasion, metastasis, hypoxia, and angiogenesis; inducing apoptosis and autophagy cell death, and enhancing the immune defense. Thus, bitter melon may serve as a promising cancer preventive and therapeutic agent.
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cancers
Review
Bitter Melon (Momordica charantia), a Nutraceutical
Approach for Cancer Prevention and Therapy
Subhayan Sur 1and Ratna B. Ray 1, 2, *
1Department of Pathology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA;
Subhayan.sur@health.slu.edu
2Cancer Center, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
*Correspondence: ratna.ray@health.slu.edu; Tel.: +1-314-977-7822
Received: 27 June 2020; Accepted: 22 July 2020; Published: 27 July 2020


Abstract:
Cancer is the second leading cause of death worldwide. Many dietary plant products show
promising anticancer eects. Bitter melon or bitter gourd (Momordica charantia) is a nutrient-rich
medicinal plant cultivated in tropical and subtropical regions of many countries. Traditionally,
bitter melon is used as a folk medicine and contains many bioactive components including
triterpenoids, triterpene glycoside, phenolic acids, flavonoids, lectins, sterols and proteins that
show potential anticancer activity without significant side eects. The preventive and therapeutic
eects of crude extract or isolated components are studied in cell line-based models and animal
models of multiple types of cancer. In the present review, we summarize recent progress in testing
the cancer preventive and therapeutic activity of bitter melon with a focus on underlying molecular
mechanisms. The crude extract and its components prevent many types of cancers by enhancing
reactive oxygen species generation; inhibiting cancer cell cycle, cell signaling, cancer stem cells,
glucose and lipid metabolism, invasion, metastasis, hypoxia, and angiogenesis; inducing apoptosis
and autophagy cell death, and enhancing the immune defense. Thus, bitter melon may serve as a
promising cancer preventive and therapeutic agent.
Keywords:
medicinal plant; bitter melon (Momordica charantia); Cucurbitaceae; signal transduction;
cancer prevention; cancer therapy
1. Introduction
Cancer is characterized by uncontrolled cell proliferation achieved by dynamic changes in the
nuclear genome [
1
3
]. Studies identify several risk factors that influence uncontrolled cell proliferation
such as: intrinsic risk arising from spontaneous mutations in DNA; external factors including
carcinogens, viruses, xenobiotic and lifestyle factors like smoking, alcohol abuse, nutrient intake,
physical activity; and endogenous factors that are related to the individual’s immune system, pattern
of metabolism, DNA damage response and hormone levels [
4
]. In the USA, the predicted cancer
incidences in the year 2020 will be around 18 lakhs, which is the equivalent of approximately 4950
new cases each day. The estimated deaths from cancer in 2020 will be around 6 lakhs corresponding
to more than 1600 deaths per day [
5
]. Although prostate, lung and colorectal cancers are the most
common cancers in men (account for 43% of all cases) and breast, lung, and colorectal cancers the most
common in women (50% of all), the incidence of other cancers in the kidney, pancreas, liver, oral cavity
and pharynx (head and neck) and skin continues to increase [
5
]. Despite significant improvement in
therapies in the past few years, cancer is the second leading cause of death, and population-based
studies project a dramatic increase in new cancer cases to more than 22 million globally by 2030 [
6
].
Thus, prevention and development of specific therapeutic agents will be key ways to manage the
disease. Studies suggested that prevention can be achieved by reducing risk from external factors and
Cancers 2020,12, 2064; doi:10.3390/cancers12082064 www.mdpi.com/journal/cancers
Cancers 2020,12, 2064 2 of 22
lifestyle factors as well as by early detection [
3
]. In case of therapy, primary tumors can generally be
removed through surgery but in some cases, surgery is dicult and not valid for sub-clinical metastases
and cannot eliminate the cancer cells, resulting in relapse. In the case of targeted therapy, over the
years more potent agents have been developed with less toxic eects, proper dosing and combination
treatment protocols. However, these methods exert side eects, are sometimes expensive and one of
the main problems is the eventual resistance of cancer cells to treatment [7].
A recent WHO report suggested that around 80% of the world population uses traditional herbal
medicine for primary healthcare needs [
8
]. Some registered drugs such as vinca alkaloids (vinblastine,
vincristine, vindesine, vinorelbine), taxanes (paclitaxel, docetaxel), podophyllotoxin and its derivations
(topothecan, irinothecan) and anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin) are
derived from natural sources [
7
]. Several epidemiological studies suggest important roles of fruits and
vegetables in reducing cancer risk [
9
]. This could be due to the cumulative eect of many bioactive
phytochemicals, vitamins, minerals, proteins and fibers in the fruits and vegetables. Many plant
products, either whole extract or bioactive components, are able to inhibit carcinogenesis, at least in
animal models. There are many ongoing clinical trials to test the safety and ecacy of natural agents
in preventing or treating cancer.
In the present review, we have focused on updated information for bitter melon
(Momordica charantia) on cancer prevention and therapy and its underlying mechanisms. Bitter melon,
bitter gourd, balsam pear or karela belongs to the family Cucurbitaceae and is widely cultivated in
Asia, Africa and South America. The medicinal value of bitter melon has been reported from ancient
times for the remedy of diseases like toothache, diarrhea, furuncle and diabetes [
10
]. The beneficial
eects of bitter melon crude extract or isolated compounds are associated with lowering diabetes
and lipidemia, anti-bacterial, antifungal and anti-HIV activities [
9
,
11
,
12
]. Promising anticancer eects
of bitter melon were seen in dierent
in vitro
and
in vivo
studies [
9
,
11
14
]. We summarize here the
molecular mechanisms of cancer prevention and therapy by bitter melon. Thus, this review has wide
implications for the management of disease that may help in progression towards clinical studies.
2. Bitter Melon and Its Constituents
Bitter melon is a bitter tasting herbaceous plant cultivated in tropical and subtropical regions of
many countries. Traditionally, bitter melon is used in dierent countries as a folk medicine. The fruits
are also used as a side dish in southeast Asia. Bitter melon tea, which is known as gohyah or herbal tea,
is made from dried slices and has been used for medicinal purposes [
10
]. Bitter melon has the highest
nutritive values among cucurbits and contains over 30 medicinal products, including carbohydrates,
proteins, fibers, vitamins (C, A, E, B1, B2, B3, and B9 as folate), and minerals (potassium, calcium, zinc,
magnesium, phosphorous and iron) [
11
13
]. The biological activity of bitter melon depends on its
major chemical constituents, including cucurbitane-type triterpenoids, cucurbitane-type triterpene
glycosides, phenolic acids, flavonoids, essential oils, fatty acids, amino acids, lectins, sterols and
saponin (goyasaponins I, II and III) constituents and some proteins present in fruits, seeds, roots,
leaves and vines [
11
]. Cucurbitane-type triterpenoids are the most prevalent chemical constituents.
The bitterness is the consequence of cucurbitane-type triterpenoids: (momordicines I (Figure 1A, #2)
and II and triterpene glycosides: momordicosides K (Figure 1B, #5), and L [
12
]. Researchers have
developed dierent extraction procedures to isolate pure compounds or plant extracts with dierent
solvents like water, methanol, ethanol, n-butanol and acetone. Organic solvents are better for the
extraction of phenolic acids and flavonoids [
15
,
16
]. There are dierent varieties of bitter melon, dierent
origins, harvest times, and depending on those parameters, the proportion of chemical constituents
varies. Dierent major constituents found in dierent varieties and dierent parts of the plants are
summarized below [11,12,17].
Cancers 2020,12, 2064 3 of 22
Cancers 2020, 12, 3 of 22
23-dimethoxy-cucurbita-5, 24-dien-19-al, 19-epoxycucurbita-6, (23E)-3β-hydroxy-,7β, 25-
dimethoxycucurbita-5, 23-diene-19-ol, 19-epoxy-19, 25-dimethoxycucurbita-6, 23-diene-3β-ol, (19R,
23E)-5β, 19-epoxy-19-methoxy cucurbita-6, 23-diene-3β, 25-diol, 25-dihydroxy-7β-methoxy
cucurbita-5, 23(E)-diene, 3β-hydroxy-7β, 25-dimethoxy cucurbita-5, 23(E)-diene, 3β, 7β, 25-
trihydroxy cucurbita-5, 23(E)-diene-19-al, 5β, 19-epoxycucurbita-6, 23(E)-diene-3β, 19, 25-triol, 5β, 19-
epoxy-19-methoxycucurbita-6,23(E)-diene-3β, 25-diol ; 3β, 25-dihydroxy-5β,19-epoxycucurbita-6,
23(E)-diene ;19(R)-methoxy-5β,19-epoxycucurbita-6, 23-diene-3β, 25-diol, 5β, 19-epoxycucurbita-6,
23(E)-diene-3β, 25-diol ; 3β, 7β-dihydroxy-25-methoxy cucurbita-5, 23(E)-diene-19-al ; 23(E)-25-
methoxy cucurbita-23-ene-3β, 7β-diol, 23(E)-cucurbita-5, 23, 25-triene-3β, 7β-diol, 23(E)-25-
dihydroxy cucurbita-5, 23-diene-3, 7-dione, 23(E)-cucurbita-5, 23, 25-triene-3, 7-dione, 23(E)-5β, 19-
epoxycucurbita-6, 23-diene-3β, 25-diol, 23(E)-5β, 19-epoxy-25-methoxy cucurbita-6, 23-diene-3β-ol ;
cucurbita-5, 23(E)-diene-3β, 7β, 25-triol, 3β-acetoxy-7β-methoxy cucurbita-5, 23(E)-diene-25-ol,
cucurbita-5(10), 6, 23(E)-triene-3β, 25-diol, cucurbita-5, 24-diene-3, 7, 23-trione ; (19R, 23E)-5β, 19-
epoxy-19-methoxy cucurbita-6, 23,25-triene-3β-ol, (23E)-3β-hydroxy-7β-methoxycucurbita-5, 23, 25-
triene-19-ol.
Figure 1. Chemical structure of some of the major components of bitter melon. (A): cucurbitane-type
triterpenoids, (B): cucurbitane-type triterpene glycosides, and (C): phenolic compounds.
2.2. Cucurbitane-Type Triterpene Glycosides:
These include momordicosides (A–E, F1, F2, G, I, K, L, M, N, O, Q, R, S and T) (Figure 1B, #5),
charantosides I–VIII (Figure 1B, #6), karaviloside (I–XI) (Figure 1B, #7), goyaglycoside- (a–h) (Figure
1B, #8), kuguaglycoside, 3-O-β-D-allopyranosyl, 7β, 25-dihydroxycucurbita-5, 23(E)-diene-19-al ; 3-
O-β-D-allopyranosyl, 7β, 25-dihydroxy cucurbita-5(6), 23(E)-diene-19-al, 3-O-β-D-allopyranosyl, 25-
methoxy cucurbita-5(6), 23(E)-diene-19-ol, 24(R)-stigmastan-3β, 5α, 6β-triol-25-ene 3-O-β-
glucopyranoside.
2.3. Phenolic Acids and Flavonoids
These include galic acid (Figure 1C, #9), tannic acid, (+)-catechin (Figure 1C, #10), epicatechin
(Figure 1C, #11), caffeic acid (Figure 1C, #12), p-coumaric, gentisic acid, and chlorogenic acid.
2.4. Proteins
Figure 1.
Chemical structure of some of the major components of bitter melon. (
A
): cucurbitane-type
triterpenoids, (B): cucurbitane-type triterpene glycosides, and (C): phenolic compounds.
2.1. Cucurbitane-Type Triterpenoids
Charantin (Figure 1A, #1), momordicine I (Figure 1A, #2), II and III, karavilagenin A (Figure 1A,
#3), B, C, D and E, kuguacins A–S (Figure 1A, #4) are major components. Other components
include: 23-dimethoxy-cucurbita-5, 24-dien-19-al, 19-epoxycucurbita-6, (23E)-3
β
-hydroxy-,7
β
,
25-dimethoxycucurbita-5, 23-diene-19-ol, 19-epoxy-19, 25-dimethoxycucurbita-6, 23-diene-3
β
-ol,
(19R, 23E)-5
β
, 19-epoxy-19-methoxy cucurbita-6, 23-diene-3
β
, 25-diol, 25-dihydroxy-7
β
-methoxy
cucurbita-5, 23(E)-diene, 3
β
-hydroxy-7
β
, 25-dimethoxy cucurbita-5, 23(E)-diene, 3
β
, 7
β
,
25-trihydroxy cucurbita-5, 23(E)-diene-19-al, 5
β
, 19-epoxycucurbita-6, 23(E)-diene-3
β
, 19, 25-triol, 5
β
,
19-epoxy-19-methoxycucurbita-6,23(E)-diene-3
β
, 25-diol; 3
β
, 25-dihydroxy-5
β
,19-epoxycucurbita-6,
23(E)-diene; 19(R)-methoxy-5
β
,19-epoxycucurbita-6, 23-diene-3
β
, 25-diol, 5
β
, 19-epoxycucurbita-6,
23(E)-diene-3
β
, 25-diol; 3
β
, 7
β
-dihydroxy-25-methoxy cucurbita-5, 23(E)-diene-19-al; 23(E)-25-methoxy
cucurbita-23-ene-3
β
, 7
β
-diol, 23(E)-cucurbita-5, 23, 25-triene-3
β
, 7
β
-diol, 23(E)-25-dihydroxy
cucurbita-5, 23-diene-3, 7-dione, 23(E)-cucurbita-5, 23, 25-triene-3, 7-dione, 23(E)-5
β
,
19-epoxycucurbita-6, 23-diene-3
β
, 25-diol, 23(E)-5
β
, 19-epoxy-25-methoxy cucurbita-6, 23-diene-3
β
-ol;
cucurbita-5, 23(E)-diene-3
β
, 7
β
, 25-triol, 3
β
-acetoxy-7
β
-methoxy cucurbita-5, 23(E)-diene-25-ol,
cucurbita-5(10), 6, 23(E)-triene-3
β
, 25-diol, cucurbita-5, 24-diene-3, 7, 23-trione; (19R, 23E)-5
β
,
19-epoxy-19-methoxy cucurbita-6, 23,25-triene-3
β
-ol, (23E)-3
β
-hydroxy-7
β
-methoxycucurbita-5,
23, 25-triene-19-ol.
2.2. Cucurbitane-Type Triterpene Glycosides
These include momordicosides (A–E, F1, F2, G, I, K, L, M, N, O, Q, R, S and T) (Figure 1B,
#5), charantosides I–VIII (Figure 1B, #6), karaviloside (I–XI) (Figure 1B, #7), goyaglycoside-
(a–h) (Figure 1B, #8), kuguaglycoside, 3-O-
β
-D-allopyranosyl, 7
β
, 25-dihydroxycucurbita-5,
23(E)-diene-19-al; 3-O-
β
-D-allopyranosyl, 7
β
, 25-dihydroxy cucurbita-5(6), 23(E)-diene-19-al,
3-O-
β
-D-allopyranosyl, 25-methoxy cucurbita-5(6), 23(E)-diene-19-ol, 24(R)-stigmastan-3
β
, 5
α
,
6β-triol-25-ene 3-O-β-glucopyranoside.
Cancers 2020,12, 2064 4 of 22
2.3. Phenolic Acids and Flavonoids
These include galic acid (Figure 1C, #9), tannic acid, (+)-catechin (Figure 1C, #10), epicatechin
(Figure 1C, #11), caeic acid (Figure 1C, #12), p-coumaric, gentisic acid, and chlorogenic acid.
2.4. Proteins
Several proteins were identified and characterized from bitter melon extract. These include
momordica antiviral protein 30kD (MAP30),
α
- and
β
-momocharin, 14-kDa Ribonucleases (RNase
MC2) and marmorin.
3. The Activity of Bitter Melon on Cancers
Bitter melon extract and its active ingredients were studied in laboratory cancer cell line-based
models and pre-clinical animal models, whereas clinical studies on cancers are lacking. The preventive
studies were conducted in animal models of blood, breast, colon, head and neck, liver, prostate,
skin and stomach cancers using mainly crude extract of bitter melon prepared by water, methanol or
ethanol. Therapeutic studies using crude extracts or isolated compounds have been conducted in
in vitro
and
in vivo
models of blood, brain, breast, colon, gastric, head and neck, kidney, liver, lung,
ovary, pancreas, prostate, skin and uterine cervical cancers. The eect of bitter melon on cancer
chemoprevention and therapy are summarized in Table 1, Figure 2and discussed below.
Cancers 2020, 12, 5 of 22
Skin
Water extract of fruit, methanol
extract of fruit and leaf, and
cucurbitane-type triterpenes
compounds from fruit
Prevented melanoma syngeneic tumor growth,
DMBA/croton oil or DMBA/peroxynitrite induced skin
carcinogenesis in mice.
[63–65]
Stomach Fruit extract, methanol extract of leaf
and fractioned proteins I–III
Showed anti-cancer activities in human gastric cancer
cell lines.
Prevented benzo(a)pyrene [B(a)P] induced forestomach
papillomagenesis in mice.
[66–68]
Uterine
cervix Leaf extract and kuguacin J Inhibited vinblastine and paclitaxel resistance in human
cervical carcinoma cell line (KB-V1). [69]
Figure 2. Types of cancer prevented by bitter melon.
3.1. Blood Cancer
The cancer preventive effect of crude bitter melon extract was first reported in a mouse model
where the ammonium acetate precipitates of bitter melon water extract prevented tumor formation
and enhanced immune function [22]. However, the crude extract showed minimum effect on normal
human peripheral blood lymphocytes as compared to lymphocytes from patients with chronic or
acute leukemia. Similarly, the bitter melon compound momordica antiviral protein 30kD (MAP30)
significantly inhibited proliferation and induced apoptosis in the human acute myeloid leukemia
(AML) cell line HL-60, THP-1 cells and patient AML cells in a dose- and time-dependent manner [18].
Fractions from seed extract, namely, Mc-1, Mc-2, Mc-3 and Mc-2Ac induced differentiation of
leukemia cell HL60 in a dose-dependent manner [19]. In another study, (9Z,11E,13E)-15,16-
dihydroxy-9,11,13-octadecatrienoic acid (15,16-dihydroxy α-eleostearic acid), which is a major
component in seeds, induced apoptosis in HL60 cells [20]. The α-eleostearic acid isolated from
ethanol extraction of seed inhibits proliferation of leukemia cell lines ED and Su9T01, whereas a
minimal effect was reported on peripheral blood mononuclear cells [21].
3.2. Breast Cancer
Both preventive and therapeutic studies were conducted on breast cancer models. The water
extract of fruit inhibited proliferation and induced apoptosis in breast cancer cells MCF-7 and MDA-
MB-231 in a time- and dose-dependent manner with 80% reduction in cell viability [27]. Importantly,
the extract showed no cytotoxic effect on primary mammary epithelial cells (HMEC) even after
treatment for five days. Like the water extract, the isolated compound MAP30 inhibited MDA-MB-
Figure 2. Types of cancer prevented by bitter melon.
Cancers 2020,12, 2064 5 of 22
Table 1. Roles of bitter melon in cancer prevention and therapy.
Cancer Model Bitter Melon Extract/Compounds Preventive and Therapeutic Eects Ref.
Blood Seed extract, water extract of fruit,
MAP30 and α-eleostearic acid
Inhibited the proliferation of leukemia cells
HL-60, THP-1, HL60 ED, Su9T01, HUT-102 and
Jurkat and induced apoptosis.
Inhibited in-vivo tumor formation in mice,
increased survival and immune function.
[1822]
Brain
MAP30, α,βmomorcharin,
charantagenins D, E, and sterol,
7-oxo-stigmasta-5,25-diene-3-O-β-
d-glucopyranoside
Inhibited proliferation, migration, invasion and
induced apoptosis in glioma cells [2326]
Breast
Water extract of fruit, dried extract
and isolated compounds
3
β
,7
β
,25-trihydroxycucurbita-5,23(E)-
dien-19-al (TCD), eleostearic acid,
RNase MC2, MAP30
Inhibited breast cancer cells growth, induced
apoptosis and autophagy.
Inhibited syngenic tumor, xenograft tumor and
spontaneous mammary tumorigenesis in SHN
virgin mice.
[13,2633]
Colon
Methanol extract of fruit, seed
extract, seed oil, α-eleostearic acid,
MAP30 and some isolated
cucurbitane-type triterpene
glycosides
Inhibited colon cancer cell proliferation,
induced cell cycle arrest, apoptosis, autophagy,
doxorubicin sensitivity and inhibited cancer
stem cells.
Prevented azoxymethane (AOM)-induced
colon carcinogenesis in F344 rats.
[13,20,26,
3439]
Head and neck Water extract of fruit
Inhibited oral cancer cell proliferation,
metabolism, and induced apoptosis in oral
cancer cells.
Regressed oral cancer syngenic tumor,
xenograft tumor and 4NQO-induced mouse
tongue carcinogenesis.
[4044]
Kidney Water extract
Inhibited adrenocortical cancer cell
proliferation, steroidogenesis and
induced apoptosis.
[45]
Liver
Water extract of fruit, methanol
extract and isolated compounds
karaviloside III, MAP30, RNase
MC2, lectin.
Inhibited murine hepatic stellate cells and
human liver cancer cells. Prevented xenograft
tumor growth in nude mice and DENA/CCl4
induced liver carcinogenesis in rats.
[13,4649]
Lung Water extract, methanol extract of
leaf, MAP30 and α-MMC.
Inhibited proliferation, migration, invasion,
and induced cell cycle arrest and apoptosis in
human lung cancer cells.
[5052]
Ovary
Water extract of fruit and kuguacin J
Inhibited growth, induced apoptosis and
cisplatin sensitivity in human ovarian cancer
invitro and invivo models.
[53,54]
Pancreas Water extract of fruit
Prevented proliferation, metabolism and
induced apoptosis in cancer cells and
xenograft tumor.
[5558]
Prostate
Water extract of fruit, leaf extract,
kuguacin J, 30 kDa protein from
seeds (MCP30)
Inhibited cell proliferation, cell cycle and
metastasis in prostate cancer cells.
Prevented xenograft tumor and spontaneous
tumor in TRAMP mice.
[5962]
Skin
Water extract of fruit, methanol
extract of fruit and leaf, and
cucurbitane-type triterpenes
compounds from fruit
Prevented melanoma syngeneic tumor growth,
DMBA/croton oil or DMBA/peroxynitrite
induced skin carcinogenesis in mice.
[6365]
Stomach Fruit extract, methanol extract of
leaf and fractioned proteins I–III
Showed anti-cancer activities in human gastric
cancer cell lines.
Prevented benzo(a)pyrene [B(a)P] induced
forestomach papillomagenesis in mice.
[6668]
Uterine cervix Leaf extract and kuguacin J Inhibited vinblastine and paclitaxel resistance
in human cervical carcinoma cell line (KB-V1). [69]
3.1. Blood Cancer
The cancer preventive eect of crude bitter melon extract was first reported in a mouse model
where the ammonium acetate precipitates of bitter melon water extract prevented tumor formation and
enhanced immune function [
22
]. However, the crude extract showed minimum eect on normal human
Cancers 2020,12, 2064 6 of 22
peripheral blood lymphocytes as compared to lymphocytes from patients with chronic or acute leukemia.
Similarly, the bitter melon compound momordica antiviral protein 30kD (MAP30) significantly inhibited
proliferation and induced apoptosis in the human acute myeloid leukemia (AML) cell line HL-60,
THP-1 cells and patient AML cells in a dose- and time-dependent manner [
18
]. Fractions from seed
extract, namely, Mc-1, Mc-2, Mc-3 and Mc-2Ac induced dierentiation of leukemia cell HL60 in a
dose-dependent manner [
19
]. In another study, (9Z,11E,13E)-15,16-dihydroxy-9,11,13-octadecatrienoic
acid (15,16-dihydroxy
α
-eleostearic acid), which is a major component in seeds, induced apoptosis in
HL60 cells [
20
]. The
α
-eleostearic acid isolated from ethanol extraction of seed inhibits proliferation
of leukemia cell lines ED and Su9T01, whereas a minimal eect was reported on peripheral blood
mononuclear cells [21].
3.2. Breast Cancer
Both preventive and therapeutic studies were conducted on breast cancer models. The water extract
of fruit inhibited proliferation and induced apoptosis in breast cancer cells MCF-7 and MDA-MB-231 in
a time- and dose-dependent manner with 80% reduction in cell viability [
27
]. Importantly, the extract
showed no cytotoxic eect on primary mammary epithelial cells (HMEC) even after treatment for
five days. Like the water extract, the isolated compound MAP30 inhibited MDA-MB-231 cells in
in vitro
and
in vivo
xenograft models in SCID mice [
70
]. Continuous administration of water extract
(0.5%) through drinking water prevented spontaneous mammary tumor development in SHN virgin
mice with no adverse side eects [
33
]. In syngeneic (mouse breast cancer cells 4T1 and E0771) and
xenograft (human breast cancer cell MDA-MB-231) mouse models, oral feeding of the extract (30%
v/v) through drinking water inhibited tumor growth, induced autophagy and reduced cholesterol
esterification [
28
,
29
]. Bitter melon extract showed better eects on triple negative breast cancer cells in
mouse models as compared to ER-positive breast cancer cells.
3.3. Colon Cancer
Bitter melon seed oil in diets regressed azoxymethane (AOM)-induced colon cancer incidence
and multiplicity in a dose-dependent manner in male F344 rats [
36
]. Free fatty acid and 9-cis, 11-trans,
13-trans-conjugated linolenic acid isolated from bitter melon seed oil reduces the cell viability of
Caco-2cells [
38
]. In addition, bitter melon seed extract in water, ethanol, or ethanol: water (1:1) showed
cytotoxic eects on human colon tumor 116 cells [
39
]. However, the water extract showed the best
eect on the cells. In addition, methanol extract of whole fruit inhibited proliferation, colony formation,
sphere formation and induced autophagy in HT-29 and SW480 cells [
34
]. The extract prepared from
whole skin showed a lower eect on the cell lines as compared to whole fruit extract. Neither of the
extracts displayed any cytotoxic eect on noncancerous human foreskin fibroblast (HFF). The extract
also increased doxorubicin sensitivity in colon cancer cells [
35
]. Konishi et al. identified the active
component 1-monopalmitin from the methanol extract that inhibits P-glycoprotein in human epithelial
colorectal adenocarcinoma cells Caco2 [
71
]. The
α
-eleostearic acid also inhibited growth of HT29 colon
carcinoma cells [20].
3.4. Gastric Cancer
Short term and long term administration of fruit extract (2.5% and 5%) inhibited benzo(a)pyrene
[B(a)P]-induced forestomach carcinogenesis in Swiss albino mice [
66
]. Long-term treatment showed
better preventive eects in mice. The methanol extract of leaf exhibited therapeutic eects on gastric
adenocarcinoma cells AGS, [
68
]. Bitter melon protein compounds (Fractioned I–III) isolated by
high-speed counter-current chromatography inhibited human gastric cancer cell line SGC-7901 [
67
].
The fraction II showed the best anticancer activity.
Cancers 2020,12, 2064 7 of 22
3.5. Head and Neck Cancer
This category includes cancers of the tongue, oral cavity, nasal cavity, paranasal sinuses,
saliva glands, larynx and pharynx. The bitter melon extract exhibited potential cytotoxic eect
in Cal27, JHU029 and JHU022 cells in a time- and dose-dependent manner [44]. The anticancer eect
was associated with inhibition of cell proliferation, induction of apoptosis, inhibition of c-Met signaling
and reduction in glycolysis and lipid metabolism [
40
,
44
]. Oral administration of the extract (30%
v/v) prevented xenograft and syngenic tumor growth by reducing cell proliferation and inducing
apoptosis in mice [
43
,
44
]. Further, in the syngenic model, the extract reduced infiltrating regulatory
T (Treg) cell populations in the tumors and in spleens [
43
]. Subsequent studies showed continuous
oral administration of water extract through drinking water (30% v/v) prevented 4-nitroquinoline
1-oxide (4-NQO)-induced mouse tongue squamous cell carcinoma development at the pre-neoplastic
stages through modulation in proliferation, ossification, metabolism and immune system [
41
].
In nasopharyngeal carcinoma cells, the Bitter melon component alpha-momorcharin (
α
-MMC) showed
cytotoxic activity on CNE-1 and HONE1 cells, whereas minimal eect was seen in non-cancerous
human nasopharyngeal epithelial cells NP69 [13].
3.6. Liver Cancer
Oral administration of methanol extract (40 mg/kg) at the pre- and post-initiation stages of
carcinogenesis prevented hepatocellular carcinoma development induced by diethylnitrosamine
(DENA) and carbon tetrachloride (CCl4) through modulation in expression of dierent genes associated
with angiogenesis, proliferation, metastasis and apoptosis [
48
]. On the other hand, treatment with the
fruit extract (5% v/v) for 48 h caused 63% cell death in HepG2 cells by inhibiting apolipoprotein B secretion
and hepatic triglyceride synthesis [
49
]. The MAP30 and
α
-MMC isolated from seeds showed potential
cytotoxic eects on HepG2 cells [
47
,
51
]. Map30 also inhibited HepG2 cell xenograft tumor growth in
nude mice [
47
]. No side eect of MAP30 was seen in the animal model. Cucurbitane-type triterpene
glycosides furpyronecucurbitane A, goyaglycoside I, charantagenin F and nine other compounds
were examined for their anti-fibrosis activity against murine hepatic stellate cells (t-HSC/Cl-6) and
anti-cancer activity against human hepatoma cells HepG2 and Hep3B [
46
]. Among the compounds,
karaviloside-III showed the best inhibitory activity against t-HSC/Cl-6, Hep3B and HepG2 cell lines.
3.7. Lung Cancer
Water extract and methanol extract of bitter melon plant leaf showed cytotoxic eects on
human non-small cell lung cells A549 and lung adenocarcinoma cells CL1 in a dose-dependent manner,
whereas normal human embryonic kidney HEK293 cells and lung WI-38 cells are less susceptible [
50
,
52
].
The
α
-MMC and MAP30 suppressed proliferation and induced S-phase cell cycle arrest and apoptosis
in A549 cells in a dose- and time-dependent manner [
51
]. The MAP30 showed more potent eects than
α-MMC on the cells.
3.8. Pancreatic Cancer
Treatment with water extract of fruit inhibited cell proliferation and induced apoptosis in
human pancreatic carcinoma cells BxPC-3, MiaPaCa-2, AsPC-1 and Capan-2 [
55
]. The extract
inhibited proliferation and induced autophagy in gemcitabine-resistant AsPC-1 cells in a dose- and
time-dependent manner [
56
]. The extract also inhibited CD44+/CD24+/EpCAMhigh pancreatic cancer
stem cell (CSC) populations, CSC-associated markers SOX2, OCT4, NANOG and CD44 in-vitro and
in-vivo, and increased sensitivity to gemcitabine [
57
]. In a xenograft model, the extract regressed
tumor volume and inhibited the glucose and lactate transporters GLUT1 and MCT4 [58].
Cancers 2020,12, 2064 8 of 22
3.9. Prostate Cancer
Oral delivery of bitter melon fruit extract prevented the progression of prostatic intraepithelial
neoplasia in TRAMP (transgenic adenocarcinoma of mouse prostate) mice by interfering with cell-cycle
progression and proliferation [
61
]. Ethanol extract of leaves in the diet (1% and 5%) prevented PC3 cell
xenograft tumor incidence without adverse eect on mouse body weight [
59
]. The same extract (0.1 and
1% in diet) increased animal survival and reduced PLS10 cell-mediated metastasis in nude mice [
60
].
Bitter melon extract induced more than 90% cell death in PC3 and LNCaP cells, whereas primary
prostate epithelial cells exhibited very modest eects [
61
]. Another study reported that whole fruit
water extract inhibits growth and induces G2-M phase cell cycle arrest of rat prostatic adenocarcinoma
cells,
in vitro
[
72
]. The ethanol extract of leaves inhibited prostate cancer growth in
in vitro
and
in vivo
models [
59
,
60
]. Bitter melon compound MAP30 (1–20
µ
g/mL) reduced cell proliferation and induced
apoptosis in human prostatic intraepithelial neoplasia (PIN) cells, PC-3 cells and LNCaP cells in a
dose-dependent manner with no cytotoxic eect on normal prostate cells RWPE-1 [
62
]. Intraperitoneal
administration of MAP30 also inhibited PC-3 xenograft tumor growth in nude mice.
3.10. Skin Cancer
Oral administration of the fruit extract prevented carcinogen-induced skin carcinogenesis in mice,
increased survival, reduced lipid peroxidation, activated the liver enzymes glutathione-S-transferase,
glutathione peroxidase and catalase, and reduced DNA damage in lymphocytes [
65
]. Similarly,
pre-treatment or continuous local application of methanol extract of fruit and leaf (at doses of
500 and 1000 mg/kg body weight) significantly reduced dimethylbenz[a] anthracene (DMBA)/croton
oil-induced skin papilloma formation, prevented micronucleus formation and chromosomal aberrations
and increased survival in Swiss albino mice [
63
]. Cucurbitane-type triterpene glycosides compounds
1 and 2 isolated from methanol extract of fruit prevented DMBA and peroxynitrite-induced mouse
skin carcinogenesis [
64
]. However, no further studies have been reported with these compounds. In a
melanoma therapeutic model, 500 and 1000 mg/kg body weight dose of fruit and leaf extracts in 50%
methanol reduced B6F10 xenograft tumor growth and increased survival of C57 B1 mice [63].
3.11. Other Cancers
Crude bitter melon extracts or isolated compounds showed potential anticancer eects on other
cancers like adrenocortical cancer, glioma, ovarian cancer and uterine cervical cancers. The extract
inhibited proliferation and induced apoptosis in human and mouse adrenocortical cancer cells,
whereas extract from blueberry, zucchini, and acorn squash did not show any cytotoxic eect [
45
].
MAP30 inhibited cell proliferation, migration and invasion and induced apoptosis in the glioma cell
lines U87 and U251 in a time- and dose-dependent manner [
23
]. The methanol extract of fruit inhibited
cell proliferation and increased cisplatin sensitivity in the ovarian cancer cell lines A2780cp, A2780s,
C13* and OV2008 [
54
]. No significant cytotoxicity of the extract was reported on immortalized human
ovarian surface epithelial (HOSE 17-1) cells. Intraperitoneal injection of the extract regressed ES2
xenograft tumor growth and increased cisplatin sensitivity in nude mice. Similarly, the ethanol extract
of leaves inhibited proliferation and induced sensitivity to the chemotherapeutic drugs vinblastine and
paclitaxel in the human cervical cancer cell line KB-V1 in a dose-dependent manner [
69
]. The hexane
and diethyl ether fractions from the extract showed the most potent eect. However, extracts from the
fruits and tendrils showed no eect on these cells. Kuguacin J (#4) isolated a methanol extract of leaf
and exhibited cytotoxicity and induced drug sensitivity on cervical cancer cells KB-VI and ovarian
cancer cells SKOV3 [
53
,
69
]. Purified lectins momordin (MW: 24 kDa) and agglutinin (MW: 32 kDa)
inhibited Ehrlichascites tumor at an LD50 dose of 5 mg per kg body weight with no apparent animal
toxicity [73].
Cancers 2020,12, 2064 9 of 22
4. Molecular Mechanism of Bitter Melon in Cancer Prevention and Therapy
The biological activity of bitter melon depends on the cumulative eect of dierent bioactive
components. The cancer preventive and therapeutic action of bitter melon crude extract/pure
compounds depends on the time of administration, i.e., pre- or post-initiation stages of carcinogenesis,
but the molecular mechanisms of prevention and therapy were found to be similar. The molecular
mechanisms of the anticancer eects of bitter melon were extensively studied in
in vitro
cancer cell
line models. Based on these studies, along with a few
in vivo
studies, the molecular mechanisms of
bitter melon are discussed below and summarized in Table 2, Figure 3.
Figure 3.
Molecular mechanisms of cancer prevention and therapy by bitter melon. Sharp arrow
indicates activation/induction and blunt arrow indicates inhibition.
4.1. Generation of Reactive Oxygen Species, Anti-Inflammation and Carcinogen Elimination
Bitter melon crude extract and pure compounds enhanced cellular reactive oxygen species (ROS)
generation, reduced inflammatory cytokines s100a9, IL23a, IL-1
β
, IL-6 and TNF
α
, and induced
activity of dierent detoxification enzymes including glutathione-s-transferase, superoxide dismutase
and catalasein in dierent cancers (Table 2). Since tumor cells have enhanced production of ROS,
further increments of ROS levels along with the induction of detoxification enzymes prevent tumor
initiation and progression and enhance stress-induced cell death. Many natural products exert similar
mechanisms of chemoprevention [
78
]. Though acute inflammation is a primary response against
pathogen or carcinogenic insult, chronic inflammation achieved by induction of the pro-inflammatory
cytokines is one of the causes of carcinogenic transformation by increasing ROS level, inducing mutation,
epithelial-to-mesenchymal transition (EMT), angiogenesis, and metastasis [
79
]. Inhibition of the
pro-inflammatory cytokines by inhibitors or neutralizing antibodies shows promising results in dierent
clinical trials [
79
]. On the other hand, detoxification enzymes including glutathione-s-transferase,
superoxide dismutase and catalase act as the first line of defense system against oxidation and
carcinogen metabolism, and thus prevent carcinogenesis initiation and progression [
80
,
81
]. Thus,
bitter melon exerts potential preventive and therapeutic eect against several cancers.
4.2. Regulation of Cell Cycle
Cancer cells are characterized by unregulated cell cycle progression and defective cell cycle check
points that contribute to uncontrolled proliferation, genetic instability and resistance to apoptotic cell
death [
82
]. Cell cycle-specific qRT-PCR arrays and subsequent validation by western blot analysis
revealed that bitter melon water extract inhibits cell cycle-promoting genes cyclin D1 and survivin
and induces tumor suppressor gene p21 and p27 in head and neck cancer cells [
44
]. The water extract
induced S or G2-M phase cell cycle arrest, inhibited expression of cyclin D1, cyclin E1 and cyclin B1
and enhanced p53, p21, and pChk1/2 in breast and prostate cancer cells [
27
,
61
]. Similar eects of crude
extract and bitter melon components
α
-MMC, MAP30, kuguacin J (#4) and lectin were observed in
other cancers (Table 2).
Cancers 2020,12, 2064 10 of 22
Table 2. Molecular mechanisms of bitter melon in cancer prevention and therapy.
Molecular Events Bitter Melon
Extract/Compound Molecular Roles Cancer Model Reference
Reactive oxygen species
(ROS) generation,
anti-inflammation,
carcinogen elimination
Fruit extract, triterpenoid
(3β,7β,25-trihydroxycucurbita-
5,23(E)-dien-19-al)
Induced ROS generation, activity of dierent
detoxification enzymes including
glutathione-s-transferase, superoxide
dismutase and catalase, and reduced
pro-inflammatory cytokines.
Head and neck cancer, lung
cancer and breast cancer cells,
alcohol-induced rat liver injury,
4NQO-induced mouse
tongue cancer
[30,40,41,50,74]
Regulation in cell cycle Fruit extract, α-MMC and
MAP30, kuguacin J, lectin
Induced G2/M phase and S phase cell cycle
arrest, inhibited cyclin D1, cyclin B1, cyclin E,
survivin, Cdk2, Cdk4 and induced p21, p27,
p53, pChk1/2
Breast cancer, prostate cancer,
colon cancer, lung cancer, and
head and neck cancer cells
[13,14,27,34,44,51,61]
Modulation in
cell signalling
Crude extract,
α
-eleostearic acid,
3β, 7β, 25-trihydroxycucurbita
-5,23(E)-dien-19-al, lectin,
RNase MC2
Inhibited c-Met/Stat3/c-myc and Mcl-1
signalling, AKT/mTOR/p70S6K signalling, p38
MAPK signalling, AMPK signalling,
AKT/ERK/FOXM1 signalling
Head and neck cancer, ovarian
cancer, breast cancer, lung cancer,
prostate cancer, nasopharyngeal
cancer and pancreatic cancer cells
[14,44,54,75]
Induction of Apoptosis
and autophagy
Crude extract, α,β-
momorcharin, RNase MC2,
3β,7β,25-trihydroxycucurbita-
5,23(E)-dien-19-al, MAP30,
lectin, BG-4
Induced activation of caspases, pro-apoptotic
genes, reduced anti-apoptotic genes, and
induced PARP cleavage.
Induced long chain 3 (LC3)-B and p62/SQSTM1
(p62), Beclin-1, ATG-7 and 12
Breast cancer, prostate cancer,
head and neck cancer, colon
cancer, lung cancer, pancreatic
cancer, hepatocellular carcinoma,
glioma, leukemia cells
[13,14,27,28,44,50,55,61,75,76]
Inhibition of cancer stem
cell population Fruit extract, MAP30
Inhibited cancer stem cells and stem cell
markers SOX2, OCT4, NANOG and CD44,
suppressed Wnt/β-catenin signalling.
Colon cancer, pancreatic cancer,
prostate cancer and glioma cells [23,34,57,62]
Inhibition of hypoxia
and angiogenesis α-MMC Reduced HIF1α, VEGF, unfolded protein
response (UPR), IRE-1, Nasopharyngeal Carcinoma [77]
Modulation in glucose
and lipid metabolism Crude extract
Inhibited key glycolysis and fatty acid
metabolism genes, phospholipid synthesis and
cholesterol esterification.
In-vivo and in-vitro model of
head and neck cancer, breast
cancer and pancreatic cancer
[29,40,58]
Modulation in
immune system Crude extract
Inhibited immune check point gene PD1,
cytokines s100a9, IL23a, IL1
β
. Induced natural
killer cell-mediated cytotoxicity. Inhibited Treg
cell and Th17 cell population.
In-vivo and in-vitro model of
head and neck cancer [4143]
Inhibition of invasion
and metastasis Crude extract, kuguacin J Inhibited MMP9, MMP2, collagenase type IV
activity, increased TIMP2
Lung adenocarcinoma cell,
ovarian cancer cell, rat prostate
cancer cells
[52,54,60]
Cancers 2020,12, 2064 11 of 22
4.3. Modulation in Cell Signaling
During cancer progression, cancer cells manipulate several signaling pathways to favor
unregulated proliferation, motility and survival [
83
]. Many of the signaling molecules have
been investigated as a potential target for cancer therapy. Bitter melon extract inhibited the
c-Met/Stat3/c-Myc/Mcl-1 axis in head and neck cancer [
44
]. The proto-oncogene MET encodes
receptor tyrosine kinase c-Met that promotes tumor development and progression by regulating
multiple downstream events including STAT3/c-Myc, PI3K/AKT, Ras/MAPK, JAK/STAT, SRC and
Wnt/
β
-catenin [
84
]. Further, the extract activated AMP-activated protein kinase (AMPK) and inhibited
the mTOR/p70S6K and/or the AKT/ERK/FOXM1 (Forkhead Box M1) signaling cascade in ovarian
cancer [
54
]. Similarly, the crude extract modulated AMPK/mTOR and p38 MAPK signaling in breast
cancer, colon cancer, and prostate cancer [
28
,
34
,
61
]. Bitter melon compounds
α
-eleostearic acid, 3
β
, 7
β
,
25-trihydroxycucurbita-5,23(E)-dien-19-al, lectin and RNase MC2 showed potential roles in regulating
signaling events in dierent cancers (Table 2). Several studies suggest that c-Met, PI3K/AKT or p38
MAPK signaling are attractive targets for drug development to inhibit proliferation and resistance
to apoptosis, and many such drugs showed promising eects in clinical trials against multiple
cancers [
84
86
]. Thus, modulation of the signaling events by bitter melon may have importance in
cancer prevention and therapy.
4.4. Induction of Apoptosis and Autophagy
Apoptosis and autophagy are considered as inter-connected pathways of cell death [
87
], and bitter
melon triggers both the pathways to induce cancer cell death. Apoptosis is caspase-mediated
programmed cell death and is activated in response to various stresses such as DNA damage,
growth factor withdrawal and oxidative stress [
87
]. Generally, solid tumors lose the ability to
undergo instantaneous and massive apoptosis, the so-called primary response that characterizes
sensitive cells due to genetic mutations or alteration [
88
]. Induction of apoptosis is a required
event for dierent classes of anticancer agents, and disruption of this mechanism can lead to
broad drug resistance and sometimes non-specific side eects [
88
]. Bitter melon crude extract
was found to enhance expression of pro-apoptotic Bax, Bak, Bid and p53, reduce anti-apoptotic
Bcl2, activate caspase 3, 7, 9, cytochrome-c release, and induce PARP cleavage in prevention of
various cancers (Table 2). Similarly, induction of apoptosis was seen by bitter melon compounds
α
,
β
- momorcharin, RNase MC2, 3
β
,7
β
,25-trihydroxycucurbita-5,23(E)-dien-19-al, MAP30, lectin and
BG-4 in dierent cancers. Autophagy is a self-degradative process in response to various stresses,
including nutrient deficiency, organelle damage, hypoxia, ROS generation, ER stress, and drug
treatment [
87
]. Autophagy mechanisms in cancer are not clear: sometimes it is pro-tumorigenic,
whereas sometimes it is beneficial for cancer prevention and excessive autophagy facilitates massive
cell death [
87
,
89
]. Bitter melon extract induced autophagic cell death by converting LC3A to lipidated
LC3B, increasing accumulation of p62, and enhancing expression of Beclin-1, ATG-7 and -12 (Table 2).
Bitter melon lectin also plays a dual role by inducing either apoptosis or autophagy [
13
]. However,
the mechanism of induction of autophagy or apoptosis in cancers following treatment with bitter
melon is not known.
4.5. Inhibition of the Cancer Stem Cell Population
Cancer stem cells are small sub-populations of cells in heterogeneous tumors and give rise to a
new tumor with the phenotype of the original one when transplanted into a host, undergo self-renewal,
dierentiation and contribute to chemotherapy or radiotherapy resistance, metastasis and tumor
relapse [
90
,
91
]. CSCs can be detected by dierent markers including Sox2, Oct4, Nanog, CD24, CD44,
CD133, CD90, EpCAM and ALDH in various tumors [
90
,
92
]. Targeting CSCs in combination with
conventional therapy is suggested to be an important approach for chemotherapy, and a number
of clinical trials are ongoing against dierent cancers [
90
]. Many natural phytochemicals exhibit
Cancers 2020,12, 2064 12 of 22
anticancer properties by targeting the CSC population and its self-renewal [
92
]. Bitter melon water
extract could inhibit CD44+/CD24+/EpCAMhigh CSC populations, decrease CSC markers SOX2, OCT4,
NANOG and CD44 and enhance gemcitabine sensitivity in pancreatic cancer models [
57
]. Similarly,
methanol extract of fruit inhibited sphere formation and expression of CSC marker DCLK1 and Lgr5 in
colon cancer cells [
34
]. MAP30 reduced expression of the self-renewal Wnt pathway eector molecule
β
-Catenin and its target genes c-Myc and cyclin D1 in glioma and prostate cancer cells [
23
,
62
]. Thus,
bitter melon may have potential therapeutic implications against dierent cancers through its action
on CSCs.
4.6. Modulation in Glucose and Lipid Metabolism
Metabolic reprogramming is one of the hallmarks of cancer that favors rapid energy production,
biosynthetic capabilities and therapy resistance. RNAseq analysis reveals down-regulation of key
glycolysis and lipid metabolism genes in prevention of mouse tongue carcinogenesis by bitter melon
water extract [
40
]. Subsequent analysis in head and neck cancer cells revealed down-regulation of key
glycolysis genes SLC2A1 (Glut-1), PFKP, LDHA, PKM and PDK3, and reduction in pyruvate and lactate
levels and glycolysis rates following treatment with the extract [
40
]. In lipid metabolism, the water
extract inhibited expression of the fatty acid biogenesis genes ACLY, ACC1 and FASN and reduced
levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and plasmenylethanolamine (pPE)
in head and neck cancer cells [
40
]. In a triple negative breast cancer (TNBC) model, the water extract
reduced esterified cholesterol by inhibiting acyl-CoA: cholesterol acyltransferase 1 (ACAT-1) [
29
].
Subsequent studies showed reduced expression of lipid metabolism genes SREBP-1/2, FASN, LDLR
and TIP47 as well as lipid droplet accumulation in the TNBC cells by the extract. Modulation of lipid
metabolism by bitter melon induced ER-stress-mediated apoptotic cell death [
29
,
40
]. Treatment with
water extract also reduced glucose transporter GLUT1 and lactate transporter MCT4 in in- vitro and
in-vivo models of pancreatic cancer [
58
]. Thus, the modulation of metabolism is an important event of
bitter melon-mediated cancer prevention and therapy.
4.7. Modulation in Immune System
Immune suppression is an important event in carcinogenesis. The bitter melon whole fruit water
extract reduced FoxP3+infiltrating regulatory T (Treg) cell populations in tumors and in spleens [
43
].
In addition, the extract reduced Th17 cell populations in tumors; however, there was no change in
the Th1 and Th2 cell populations. Further, treatment with the extract enhanced natural killer (NK)
cell-mediated cytotoxic eects in head and neck cancer cells [
42
]. However, the extract did not show any
cytotoxic eect on the NK cells, but enhanced granzyme B accumulation, translocation/accumulation
of CD107a/LAMP1 and expression of CD16 and NKp30. RNA sequence analysis revealed that the
water extract significantly modulates the "immune system process" in the prevention of mouse tongue
carcinogenesis [
41
]. The significantly down-regulated genes of this pathway were s100a9, IL23a, IL1
β
and the immune checkpoint gene PDCD1/PD1 in the bitter melon-treated group. Elevated expression of
s100a9, IL23a, IL1
β
and PD1 were observed in several human malignancies. Pharmaceutical targeting
of s100a9 or PD1 showed promising results in phase I–III clinical trials against dierent cancers [
93
95
].
Thus, bitter melon extract shows a potential role in cancer prevention and therapy.
4.8. Inhibition of Invasion, Metastasis, Hypoxia and Angiogenesis
Bitter melon water extract inhibited wound healing, migration and invasion in ovarian cancer
cell line SKOV3 [
54
]. Methanol extract of bitter melon leaf inhibited migration and invasion and
suppressed enzymatic activity of MMP-2 and MMP-9 in human lung adenocarcinoma CL1 cells [
52
].
Similarly, ethanol extract of leaf inhibited migration and invasion of rat prostate cancer cells (PLS10) by
inhibiting MMP-2, MMP-9, urokinase plasminogen activator (uPA) and collagenase type IV activity
and by inducing expression of TIMP2 [
60
]. The bitter melon component
α
-MMC reduced expression
Cancers 2020,12, 2064 13 of 22
of hypoxia-inducible factor 1-alpha (HIF1
α
) and vascular endothelial growth factor (VEGF) in hypoxic
nasopharyngeal carcinoma cells, and inhibited growth of human umbilical vein endothelial cells [
77
].
All together, bitter melon extract or pure compounds modulate multiple cellular events at a
time to prevent cancer cell proliferation, survival and metastasis. How the extract or its compounds
regulate dierent events simultaneously to exhibit anticancer eects is, however, unclear. The possible
mechanisms of bitter melon and its compounds in this regard are discussed below.
4.9. How Does Bitter Melon Extract Enter into Cancer Cells?
To execute anticancer activity, bitter melon extract/compounds must interact with the cancer cell
membrane and thereafter enter cancer cells. Little is known about this mechanism. In one study,
it was evident that bitter melon water extract could inhibit expression of membrane lipid raft protein
Flotilin and modulate its localization in head and neck cancer cells [
40
]. In the same study, bitter melon
extracts reduced levels of cell membrane components phosphatidylcholine, phosphatidylethanolamine,
and plasmenylethanolamine in head and neck cancer cells. This indicates that the extract might interact
with the lipid bilayer and regulate cancer cell membrane integrity and permeability. Lipid rafts are also
receptor-mediated cell signaling hubs. Thus, bitter melon-mediated modulation in dierent signaling
events might be due to modulation of membrane lipid rafts. Lectin-type compounds are found to
bind specifically to cell surface oligosaccharides and glycan, and are transported into cells [
96
,
97
].
Cancer cells modulate their membrane structure from normal cells in many ways. Among them,
alteration in membrane oligosaccharides is observed predominantly in cancer cells [
97
]. Dierent types
of lectins are present in bitter melon extract, which may act similarly to enter specifically into cancer
cells and exhibit biological mechanisms including inhibition of ribosomes and induction of apoptotic
and autophagic cell death [
96
,
98
]. Dierent triterpene glycosides bind to cell membranes, interact with
membrane lipids and form glycoside–sterol complexes in the membrane, resulting in the formation of
multimeric channels in sterol-containing lipid bilayers and increased permeability of membranes to
ions and peptides [
99
]. Saponin types of compounds also have the ability to bind to the cell surface,
to form pores in the membrane and disrupt the ionic balance in the membrane, resulting in cell
lysis [
100
]. Similarly, flavonoids can easily bind to the cell surface, enter the cells and exhibit cytotoxic
eects [
101
]. Thus, it seems that types of triterpene glycosides, saponins and flavonoids present in
bitter melon may act by similar mechanisms to enter into cells and show anticancer eects. However,
detailed studies are needed to know the exact mechanisms by which bitter melon extract modulates
membrane integrity and thereafter enters into cells to show biological eects.
4.10. How Does Bitter Melon Regulate Gene Function?
Bitter melon extract and its compounds suppress the function of oncogenes and induce expression
of tumor suppressive genes at a time to exhibit anticancer eect. Next generation RNAseq analysis
showed that 4482 genes were dierentially regulated in the prevention of mouse tongue cancer by
bitter melon [
41
]. Subsequent analysis revealed that the genes significantly regulate multiple biological
processes including “signal transduction,” “apoptosis process,” “metabolic process,” “cell adhesion,”
“lipid metabolism,” “immune system process,” “angiogenesis,” “ossification,” and “G1/S transition
of mitotic cell cycle.” An antibody array from bitter melon extract-treated breast cancer cells showed
significant inhibition of survivin, XIAP, claspin and Bcl2 proteins and up-regulation of catalase, Bax and
p27 proteins [27]. The underlying mechanism may include:
4.10.1. Interaction with Cellular Macromolecules DNA, RNA and Proteins
Bitter melon components
α
-MMC and MAP30 have DNase activity and topological inactivation of
DNA activity [
102
]. These two components were found to be potent inhibitors of protein synthesis due
to their ribosome-specific N-glycosidase activity [
102
]. The RNases MC2, found in bitter melon seed,
showed potent RNA-cleavage activity toward baker’s yeast tRNA, tumor cell rRNA, and an absolute
specificity for uridine [
75
]. In the same study, RNase MC2 induced nuclear damage by karyorrhexis,
Cancers 2020,12, 2064 14 of 22
chromatin condensation and DNA fragmentation, resulting in early/late apoptosis in the breast cancer
cell line MCF7 [
75
]. Bitter melon lectins have type I and II ribosome inactivation activity [
22
,
98
].
Another study showed that a purified factor from bitter melon extract (molecular weight corresponding
to 40 kDa) inhibits RNA and protein synthesis in intact tissue culture cells [
103
]. A protein component
(molecular weight corresponding to 50–70 kDa) present in water extract showed non-competitive
inhibition of guanylate cyclase [
22
]. Bitter melon extract exhibits P-glycoprotein inhibitory activity [
37
].
ABC transporter P-glycoprotein is highly expressed in tumor cell membranes and excretes hydrophobic
drugs from the cells in an ATP-dependent manner, resulting drug resistance [
37
]. Bitter melon extract
inhibits the activity of calcium-independent phospholipase A2 (iPLA2) in head and neck cancer
cells [
40
]. iPLA2 is ubiquitously expressed in mammalian cells and participates in several biological
processes including lipid metabolism, phospholipid remodeling, cell dierentiation, maintenance of
mitochondrial integrity, cell proliferation, signal transduction and cell death [
40
]. Studies suggest that
flavonoids physically interact with DNA, RNA and protein molecules, thereby regulating transcription,
translation, protein function and enzymatic activity [
104
,
105
]. The flavonoids form strong hydrogen
bonds, enabling them to bind strongly with nucleic acids and proteins. Bitter melon extract contains
several flavonoids; it seems that those components may act in a similar way. There is no study
indicating how bitter melon components enter the nucleus. All the evidence indicates that bitter melon
components enter cells and regulate the functions of DNA, RNA and protein in cancer prevention
and therapy.
4.10.2. Epigenetic Modification
Epigenetic regulation, including DNA methylation at CpG dinucleotide sequences, histone
modifications such as methylation and acetylation, and non-coding RNA-mediating regulation,
are reversible processes and play crucial roles in gene expression. Epigenetic changes are essential
events that regulate activation of oncogenes and suppression of tumor suppressor genes, and are widely
seen at early stages of carcinogenesis [
106
]. Many medicinal plant extracts and active components can
reverse epigenetic modifications, thereby exhibiting anticancer properties [
107
]. The role of bitter melon
in epigenetic modification is not well studied. Bitter melon extract contains many phytochemicals,
particularly flavonoids. Flavonoids were found to alter epigenetic mechanisms in the restriction
of cancer [
108
]. A bitter melon triterpenoid, 3
β
,7
β
,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD),
inhibits histone deacetylases (HDAC1, HDAC2, HDAC3 and HDAC4) in the prevention of breast
cancer cell growth [
30
]. Bitter melon MCP30 inhibits histone deacetylase-1 (HDAC-1) activity and
promotes histone H3 and H4 acetylation in prostate cancer cells [
62
]. MAP30 induces p300, a histone
acetyltransferase, and promotes histone H3 acetylation in leukemia cells [
18
]. Bitter melon fruit extract
shows anti-inflammatory eects in human lung epithelial cells by upregulating micro RNAs miR-221
and miR-222 [
109
]. This indicates that regulation in gene expression by bitter melon might be due to
epigenetic modification activity; however, detailed studies are needed to elucidate these mechanisms.
5. Conclusions
As discussed in this review, bitter melon is rich in many nutrients and active components including
triterpenoids, triterpene glycoside, phenolic acids, flavonoids, lectins, sterols, proteins and saponins.
The cancer preventive and therapeutic ecacy of bitter melon was extensively studied using crude
extract in water, methanol and ethanol as solvents. Both crude extract and isolated compounds have
potential cancer preventive and therapeutic eects to inhibit cancer cell proliferation, survival and
metastasis against several cancers without any significant toxicity in normal cells. The anticancer
eects are associated with ROS generation, activation of detoxification enzymes, inhibition of cancer
stem cell populations and their self-renewal, inhibition of cell cycle, cell signaling, invasion, metastasis,
hypoxia, angiogenesis, glucose and lipid metabolism, induction of apoptosis and autophagy and
modulation in the immune system (Figure 3). Alterations in multiple cellular events may be achieved
simultaneously due to modulation of membrane organization, interaction with DNA, RNA and
Cancers 2020,12, 2064 15 of 22
proteins, and epigenetic modifications by bitter melon (Figure 3). Thus, it seems that bitter melon
may improve cancer preventive machinery. On the other hand, the extracts or pure compounds
may be used as therapeutic agents alongside conventional therapy for additional cancer treatment
management. However, further evaluation of active components and in-depth mechanistic study in
pre-clinical systems are needed, which may have importance for designing prospective studies for
interventional therapies.
6. Future Directions
Bitter melon extract is considered as a popular health drink despite its bitter taste. Bitter melon
is rich in nutrients and bio-active components. The crude extract and some isolated compounds
have been studied against dierent cancers in cell culture and pre-clinical animal models; however,
we still need to identify whether these isolated compounds possess similar eects to crude bitter
melon extract or not. We also do not know whether mixture of some of those compounds will be
more ecacious or not. More preclinical studies are needed for in-depth evaluation of therapeutic
ecacy. Some ambiguities in dierent studies are present due to dierent methods of extraction,
dierent varieties of fruits and dierent doses. There is a lack of information about metabolism and
bioavailability of the compounds discovered. Further, there are limited studies using the same purified
compounds in dierent cancer preclinical models, raising questions about the specificity of the active
components. Preventive roles of bitter melon in many cancers are well-studied in pre-clinical models;
however, anticancer studies using bitter melon as a combination with standard therapy are also limited.
Thus, there is an opportunity to explore these research areas and carefully design the clinical studies to
fight against cancer.
Author Contributions:
S.S. and R.B.R. conceived and wrote the manuscript. All authors have read and agreed to
the published version of the manuscript.
Funding: This work was supported by research grant R01 DE024942 from the National Institutes of Health.
Acknowledgments:
The authors like to thank Joel Eissenberg for editing this manuscript and Kalyan Venkata for
helping us to draw the chemical structures at chemdraw.
Conflicts of Interest: The authors of this manuscript declare no conflicts of interest
Abbreviations
ROS Reactive oxygen species
αMMC α-Momorcharin
MAP30 Momordica Antiviral Protein 30kD
iPLA2 calcium-independent phospholipase A2
DMBA 7, 12-Dimethylbenz(a)anthracene
4NQO 4-Nitroquinoline 1-oxide
ER Endoplasmic Reticulum
c-Met MET Proto-Oncogene
DENA Diethylnitrosamine
CCl4Carbon tetrachloride
AMPK 50-AMP-Activated Protein Kinase
AKT AKT Serine/Threonine Kinase
mTOR Mechanistic Target of Rapamycin Kinase
TRAMP Transgenic Adenocarcinoma of the Mouse Prostate
TNFαTumor Necrosis Factor α
IL23a Interleukin 23 Subunit Alpha
IL1βInterleukin 1 Beta
IL6 Interleukin 6
SOX2 SRY-Box transcription Factor 2
OCT4 Octamer-binding transcription factor 4
Cancers 2020,12, 2064 16 of 22
Cdk2/4 Cyclin Dependent Kinase 2/4
MAPK Mitogen-Activated Protein Kinase
ERK Extracellular signal-regulated kinase
FOXM1 Forkhead box protein M1
RAC RacFamily Small GTPase
CDC42 Cell division control protein 42 homolog
PARP Poly (ADP-ribose) polymerase
Bax BCL2-Associated X, Apoptosis Regulator
Bak Bcl-2 homologous antagonist/killer
Bid BH3-Interacting Domain Death Agonist
Bcl2 BCL2 Apoptosis Regulator
LC3-B Microtubule-Associated Protein 1 Light Chain 3 Beta
ATG-7/12 Autophagy-Related 7/12
MMP2/9 Matrix Metallopeptidase 2
TIMP2 TIMP Metallopeptidase Inhibitor 2
HIF1αHypoxia-inducible factor 1-alpha
VEGF Vascular endothelial growth factor
UPR Unfolded Protein Response
IRE-1
The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1
α
GLUT-1 Glucose transporter 1
SLC2A1 Solute Carrier Family 2 Member 1
PFKP Phosphofructokinase Platelet
MCT4 Monocarboxylate transporter 4
LDHA Lactate dehydrogenase A
PKM Pyruvate kinase isozymes M1/M2
PDK3 Pyruvate Dehydrogenase Kinase 3
ACLY ATP Citrate Lyase
ACC1 Acetyl-CoA carboxylase 1
FASN Fatty Acid Synthase
SREBP Sterol regulatory element-binding protein
LDLR Low density lipoprotein receptor
ACAT-1 Acyl-Coenzyme A: Cholesterol Acyltransferase 1
TIP47 Tail-interacting protein of 47 kDa
PD1 Programmed cell death-1
LAMP1 Lysosomal-associated membrane protein 1
CD107a Cluster of Dierentiation 107a
Treg Regulatory T cells
Th 17 cells T-helper 17 cells.
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2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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... a and ß carotene, zeaxanthin, and lutein are the antioxidants which are present in great amounts in bitter gourd [6]. A rich quantity of vitamin A also occurs with these antioxidants that protects the body from free radicals and prevents premature aging and other problems [7][8][9]. Our research group has formerly explored the antimicrobial potential of M. charantia leaf extracts against Staphylococcus aureus and Pseudomonas aeruginosa under the influence of magneto priming [8]. ...
... Traditionally, bitter melon is used in different countries as a folk medicine. The fruits are also used as a side dish in southeast Asia (Sur et al., 2020). Bitter gourd has a higher nutritional value. ...
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Bitter gourd (Momordica charantia L.) is an important cucurbitaceous vegetable due to its high nutritional value. Different growth regulators were used for the better yield of bitter gourd but the application of gibberellic acid as foliar spray is less addressed. An experiment was conducted to investigate the effect of gibberellic acid (GA3) on the yield and growth stages of bitter gourd at Horticulture Research Farm, The University of Agriculture Peshawar, Pakistan during summer 2016. Gibberellic acid concentrations (GA3) 0 ppm, 30 ppm, 60 ppm, and 90 ppm were applied at different leaf stages i.e., 2-4 leaves, 5-7 leaves, and 8-10 leaves. Results revealed that both the growth and yield were significantly influenced by the application of GA3 concentrations at different growth stages. Furthermore, the use of 90 ppm GA3 concentration improved the minimum male to female ratio (2.19), maximum number of fruits plant-1 (20.22), fruit length (15.64 cm), fruit diameter (3.51 cm), fruit weight plant-1 (137.82 g), fruit yield kg plot-1 (13.98 kg), and total yield tons ha-1 (38.83 t) respectively. While 30 ppm GA3 improved the minimum days to first flower (31.22) and minimum days to first harvest (48.56). However, regarding the growth stages 8-10 leaf stage improved minimum days to first flower (33.33), minimum days to first harvest (50.33), minimum male to female ratio (2.81), and maximum number of fruits plant-1 (18.50), number of branches plant-1(4.67), fruit length (15.00 cm), fruit diameter (3.29 cm), fruit weight plant-1 (137.19 g), fruit yield kg plot-1 (12.79 kg), and total yield tons ha-1 (35.53 t). Overall gibberellic acid at 90 ppm concentration at 8-10 leaf stages was found beneficial for better growth and yield of bitter gourd under the semi-arid climatic condition of Peshawar.
... Cucurbitaceae has traditionally been used for medical nutritional therapy and medicine in many areas (Sur et al. 2020). Bioactive compounds, including flavonoids, phenols, terpenoids, saponins, sterols, and glycosides, have been isolated from the fruits, leaves, and seeds of M. charantia (Jia et al. 2017). ...
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Background Momordica charantia is a member of the Cucurbitaceae family and has traditionally been used for medical nutritional therapy to cure diabetes, and its various biological properties have been reported. However, several studies have demonstrated that M. charantia may exert toxic or adverse effects under different conditions. In this study, we prepared an M. charantia extract using ultrasound-assisted extraction, which is a green technology, and verified its anti-inflammatory effects. Objectives The aim of this study was to investigate the anti-inflammatory effects of M. charantia extract using ultrasound-assisted extraction in LPS-induced Raw264.7 macrophages and explore the potential mechanism mediated by the MAPK/NF-κB signaling pathway. Results We found that the M. charantia extract was non-toxic up to a concentration of 500 μg/mL in Raw264.7 cells. We verified that treatment with M. charantia extract significantly reduced the production of nitric oxide and proinflammatory cytokines, including TNF-α, IL-1β, IL-2, and IL-6, in LPS-stimulated RAW264.7 cells. Moreover, the anti-inflammatory cytokine IL-10 was dramatically increased by treatment with the M. charantia extract. In addition, the phosphorylation of the transcription factor NF-κB, which modulates the production of inflammatory proteins, including JNK, ERK, and p38, was reduced by downregulation of the MAPK signaling pathway. Conclusion These results indicate that the M. charantia extract collected using an industrial ultrasonic system is non-toxic and has an anti-inflammatory effect through regulation of the NF-κB and MAPK pathways, suggesting that it can act as a therapeutic candidate for the treatment of inflammatory diseases.
... Alpha-momorcharin (αMMC) is a typical type I RIP, extracted from Momordica charantia, that removes a specific adenine from 28S rRNA and inhibits protein biosynthesis (Puri et al., 2009). Numerous studies have shown that αMMC exhibits several medicinal properties, including antitumor, antidiabetic, antimicrobial, and antiviral activities, and exhibits an immune-modulatory effect both in vitro and in vivo (Sur & Ray, 2020 ). Recent studies have found that foliar spraying of αMMC on leaves not only enhanced the defence response of tobacco plants to a variety of pathogens, but also could strengthen crop (M. ...
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Many host factors of plants are used by viruses to facilitate viral infection. However, little is known about how alpha‐momorcharin (αMMC) counters virus‐mediated attack strategies in tomato. Our present research revealed that the 2b protein of cucumber mosaic virus (CMV) directly interacted with catalases (CATs) and inhibited their activities. Further analysis revealed that transcription levels of catalase were induced by CMV infection and that virus accumulation increased in CAT‐silenced or 2b‐overexpressing tomato plants compared with that in control plants, suggesting that the interaction between 2b and catalase facilitated the accumulation of CMV in hosts. However, both CMV accumulation and viral symptoms were reduced in αMMC transgenic tomato plants, indicating that αMMC engaged in an antiviral role in the plant response to CMV infection. Molecular experimental analysis demonstrated that αMMC interfered with the interactions between catalases and 2b in a competitive manner, with the expression of αMMC inhibited by CMV infection. We further demonstrated that the inhibition of catalase activity by 2b was weakened by αMMC. Accordingly, αMMC transgenic plants exhibited a greater ability to maintain redox homeostasis than wild‐type plants when infected with CMV. Altogether, these results reveal that αMMC retains catalase activity to inhibit CMV infection by subverting the interaction between 2b and catalase in tomato. Alpha‐momorcharin directly disrupts the interaction between catalase and 2b by competing with 2b in binding to catalases, altering cellular redox homeostasis, reducing toxic reactive oxygen species production, and augmenting resistance against cucumber mosaic virus infection.
... The anti-cancer activity of M. charantia or its components is exerted through a variety of mechanisms viz. regulation of cell signaling, activation of reactive oxygen species (ROS), regulation of glucose and lipid metabolism, hypoxia, inhibition of invasion and angiogenesis, induction of apoptosis, and augmentation of immune defense system (Sur and Ray 2020). The anti-leukemic potential of M. charantia was first established in 1971 by West and colleagues (West et al. 1971). ...
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Myeloid leukemia is one of the major causes of deaths among elderly with very poor prognosis. Due to the adverse effects of existing chemotherapeutic agents, plant-derived components are being screened for their anti-leukemic potential. Momordica charantia (bitter gourd) possesses a variety of therapeutic activities. We have earlier demonstrated anti-leukemic activity of acetone extract of M. charantia seeds. The present study reports purification of differentiation inducing principle(s) from further fractionated seed extract (hexane fraction of the acetone extract, Mc2-Ac-hex) using HL-60 cells. Out of the 5 peak fractions (P1-P5) obtained from normal phase HPLC of the Mc2-Ac-hex, only peak fraction 3 (P3) induced differentiation of HL-60 cells as evident from an increase in NBT-positive cells and increased expression of cell surface marker CD11b. The P3 differentiated the HL-60 cells to granulocytic lineage, established by increased CD15 (granulocytic cell surface marker) expression in the treated cells. Further, possible molecular mechanism and the signalling pathway involved in the differentiation of HL-60 cells were also investigated. Use of specific signalling pathway inhibitors in the differentiation study, and proteome array analysis of the treated cells collectively revealed the involvement the of ERK/MAPK mediated pathway. Partial characterization of the P3 by GC-MS analysis revealed the presence of dibutyl phthalate, and derivatives of 2,5-dihydrofuran to be the highest among the 5 identified compounds. This study thus demonstrated that purified differentiation-inducing principle(s) from M. charantia seed extract induce HL-60 cells to granulocytic lineage through ERK/MAPK signalling pathway. Supplementary information: The online version contains supplementary material available at 10.1007/s10616-022-00547-x.
... Momordica charantia is a plant-like plant that has often been used as a medicine since time immemorial. This climbing plant belongs to the squash family, commonly known as bitter gourd or bitter melon in English and Carla in Bengali [20]. ...
... MAP30 and α-MMC is a single chain RIP (type I ribosome-inactivating proteins) and their molecular mass are 30 kD. MAP30 and α-MMC prevent many types of cancers such as blood, brain, breast, colon, liver, and lung cancer [85]. In addition, polypeptide-P, a hypoglycemic peptide, has an imperative function in the recognition of cells and certain reactions required for the adhesion purpose [30]. ...
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Background Melatonin is a multi-functional molecule widely employed in order to mitigate abiotic stress factors, in general and salt stress in particular. Even though previous reports revealed that melatonin could exhibit roles in promoting seed germination and protecting plants during various developmental stages of several plant species under salt stress, no reports are available with respect to the regulatory acts of melatonin on the physiological and biochemical status as well as the expression levels of defense- and secondary metabolism-related related transcripts in bitter melon subjected to the salt stress. Results Herewith the present study, we performed a comprehensive analysis of the physiological and ion balance, antioxidant system, as well as transcript analysis of defense-related genes ( WRKY1 , SOS1, PM H + -ATPase, SKOR, Mc5PTase7 , and SOAR1 ) and secondary metabolism-related gene expression ( MAP30, α-MMC , polypeptide-P , and PAL ) in salt-stressed bitter melon ( Momordica charantia L.) plants in response to melatonin treatment. In this regard, different levels of melatonin (0, 75 and 150 µM) were applied to mitigate salinity stress (0, 50 and 100 mM NaCl) in bitter melon. Accordingly, present findings revealed that 100 mM salinity stress decreased growth and photosynthesis parameters (SPAD, Fv / Fo , Y(II)), RWC, and some nutrient elements (K ⁺ , Ca ²⁺ , and P), while it increased Y(NO), Y(NPQ), proline, Na ⁺ , Cl ⁻ , H 2 O 2 , MDA, antioxidant enzyme activity, and lead to the induction of the examined genes. However, prsiming with 150 µM melatonin increased SPAD, Fv / Fo , Y(II)), RWC, and K ⁺ , Ca ²⁺ , and P concentration while decreased Y(NO), Y(NPQ), Na ⁺ , Cl ⁻ , H 2 O 2 , and MDA under salt stress. In addition, the antioxidant system and gene expression levels were increased by melatonin (150 µM). Conclusions Overall, it can be postulated that the application of melatonin (150 µM) has effective roles in alleviating the adverse impacts of salinity through critical modifications in plant metabolism.
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The recent trend in infectious diseases and chronic disorders has dramatically increased consumers' interest in functional foods. As a result, the research of bioactive ingredients with potential for nutraceutical and food application has rapidly become a topic of interest. In this optic, the plant Momordica charantia (M. charantia) has recently attracted the most attention owing to its numerous biological properties including anti-diabetic, anti-obesity, anti-inflammatory, anti-cancers among others. However, the current literature on M. charantia has mainly been concerned with the plant extract while little is known on the specific bioactive compounds responsible for the plant's health benefits. Hence, the present review aims to provide a comprehensive overview of the recent research progress on bioactives isolated from M. charantia, focusing on polysaccharides, proteins, and triterpenoids. Thus, this review provides an up-to-date account of the different extraction methods used to isolate M. charantia bioactives. In addition, the structural features and biological properties are presented. Moreover, this review discusses the current and promising applications of M. charantia bioactives with relevance to nutraceutical and food applications. The information provided in this review will serve as a theoretical basis and practical support for the formulation of products enriched with M. charantia bioactives.
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Excessive use of metaldehyde to combat mollusks directly or indirectly endangers non-targeted organisms. The present study aimed to reveal the antitoxic potential of bitter melon (Momordica charantia L.) extract (BME) against metaldehyde-related toxicity in Allium cepa L. The experimental groups formed using A. cepa bulbs were exposed to aqueous solutions containing 350 mg/L BME, 700 mg/L BME, 200 mg/L metaldehyde, 200 mg/L metaldehyde +350 mg/L BME and 200 mg/L metaldehyde +700 mg/L BME, respectively. The bulbs in the control group dipped in tap water. Metaldehyde suppressed growth with respect to germination ratio, root elongation and weight gain parameters. In metaldehyde-administered group, mitotic index (MI) was reduced, while the frequencies of micronucleus (MN) and chromosomal aberrations (CAs) increased. Metaldehyde promoted CAs such as sticky chromosomes, vagrant chromosome, fragment, unequal distribution of chromatin, reverse polarization, bridge and multipolar anaphase in root tip meristem cells. Spectral shift and molecular docking confirmed the genotoxic effect of metaldehyde resulting from DNA-metaldehyde interaction. The DNA damage in root meristems was revealed using the Comet Assay. Metaldehyde stress provoked oxidative stress. Activities superoxide dismutase (SOD) and catalase (CAT) enzymes along with level of malondialdehyde (MDA) accumulation accelerated. In roots treated with metaldehyde, epidermis cell damage, flattened cell nucleus, cortex cell damage and cortex cell wall thickening were observed as meristematic cell damage. BME attenuated metaldehyde-induced toxicity in a dose-dependent manner. This study demonstrated the mitigative potential of plant derived BME with no-to-low side effects against hazardous chemicals including metaldehyde. Nature is the most valuable weapon against toxicity from pollutants. Therefore, the protective potential of BME against other harmful agents should be screened.
Chapter
Momordica charantia L. (MC, bitter melon) is a cultivated plant from the family Cucurbitaceae. Regarding metabolomics and phytochemical studies, it has phenolic compounds, terpenoids, saponins, peptides and proteins, and polysaccharides as main constituents with pharmacological effects. Preclinical and clinical studies exhibited numerous biological activities attributed to MC or its constituents. Antidiabetic, cardioprotective, antidyslipidemia, antiobesity hypotensive, antioxidant, anti-inflammatory, hepatoprotective, renoprotective, neuroprotective, anticancer antiviral, antibacterial, antifungal, anthelmintic, antimalarial, and wound healing are significant beneficial properties of MC and its ingredients. Although its safety and toxicity are not vastly studied in clinical trials, some adverse clinical manifestations have been reported afterward its consumption. Modification of its bioavailability by fabrication of nanotechnology-based formulations and conducting more clinical trials for investigation of its efficacy and toxicity are the future prospects.KeywordsCucurbitaceaePhytochemicals Momordica charantia Bitter melonBitter gourdPharmacological applicationsChemical components
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Recently, reactive oxygen species (ROS), a class of highly bioactive molecules, have been extensively studied in cancers. Cancer cells typically exhibit higher levels of basal ROS than normal cells, primarily due to their increased metabolism, oncogene activation, and mitochondrial dysfunction. This moderate increase in ROS levels facilitates cancer initiation, development, and progression; however, excessive ROS concentrations can lead to various types of cell death. Therefore, therapeutic strategies that either increase intracellular ROS to toxic levels or, conversely, decrease the levels of ROS may be effective in treating cancers via ROS regulation. Chinese herbal medicine (CHM) is a major type of natural medicine and has greatly contributed to human health. CHMs have been increasingly used for adjuvant clinical treatment of tumors. Although their mechanism of action is unclear, CHMs can execute a variety of anticancer effects by regulating intracellular ROS. In this review, we summarize the dual roles of ROS in cancers, present a comprehensive analysis of and update the role of CHM—especially its active compounds and ingredients—in the prevention and treatment of cancers via ROS regulation and emphasize precautions and strategies for the use of CHM in future research and clinical trials.
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Experiments conducted in vitro and in vivo, as well as some preclinical trials for cancer therapeutics, support the antineoplastic properties of lectins. A screening of antitumoral activity on HT29 colon cancer cells, based on polypeptide characterization and specific lectin binding to HT29 cells membrane receptors, was performed in order to assess the bioactivities present in four Mediterranean plant species: Juniperus oxycedrus subsp. oxycedrus, Juniperus oxycedrus subsp. badia, Arbutus unedo and Corema album. Total leaf proteins from each species were evaluated with respect to cell viability and inhibitory activities on HT29 cells (cell migration, matrix metalloproteinase –MMP proteolytic activities). A discussion is presented on a possible mechanism justifying the specific binding of lectins to HT29 cell receptors. All species revealed the presence of proteins with affinity to HT29 cell glycosylated receptors, possibly explaining the differential antitumor activity exhibited by the two most promising species, Juniperus oxycedrus subsp. badia and Arbutus unedo.
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