The document reviews the anticancer mechanisms of the natural compound cucurbitacin from Cucurbitaceae plants. It summarizes that cucurbitacins induce tumor cell apoptosis through multiple pathways, including the STAT3, MAPK, NF-κB, and PI3K/AKT signaling pathways. It also discusses how cucurbitacins promote cytoskeletal destruction and cell cycle arrest. Studies show cucurbitacins exert anticancer effects by multi-targeting various cancer-related signaling pathways and have potential as anticancer drugs.

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Traditional Chinese Medicine
Advances in research on the anticancer mechanism of the natural
compound cucurbitacin from Cucurbitaceae plants: a review
Jing Liang1
, Dan Chen1
*
1
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
*Corresponding to: Dan Chen, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical
University, No. 22, Qixiangtai Road, Heping District, Tianjin, China. E-mail: ilvcd@163.com.
Highlights
This review summarizes the advances in research on cucurbitacins B, D, E, and I in inducing tumor cell
apoptosis, cytoskeletal destruction, cell cycle arrest, and autophagy and in regulating various cancer-related
signaling pathways.
Traditionality
Cucurbitacins are present in some traditional Chinese herbs (TCH) such as Gualou (Fructus Trichosanthis),
Tianhuafen (Radix Trichosanthis), and Tianguadi (Pedicellus Melo). An ancient book named Shennong
Bencao Jing (1602 A.D., Donghan Dynasty of China) has reported that TCH Tianguadi (Pedicellus Melo)
and the dried fruit stalk of Cucumis melo L. have been used for treating jaundice because components
present in these herbs induce vomiting and aid in expelling phlegm.

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Abstract
Cucurbitacins are highly oxidized tetracyclic triterpenoids that are widely found in plants belonging to
Cucurbitaceae family and exert various pharmacological effects. Many cucurbitacin derivatives are available, of
which cucurbitacins B, D, E, and I are important members of the cucurbitacin family and exert anticancer effects
against various cancers. This review summarizes the advances in research on cucurbitacins B, D, E, and I in
inducing tumor cell apoptosis, cytoskeletal destruction, cell cycle arrest, and autophagy and in regulating various
cancer-related signaling pathways. In addition, this review summarizes the latest research on the synergistic
effects of the combination of cucurbitacins and clinically approved chemotherapeutic drugs. The findings
summarized in this review suggest that cucurbitacins are multi-targeting and multi-functional anticancer drugs
and that their complex anticancer mechanisms should be examined in future studies. Because of their proven
benefits, cucurbitacins have the potential to be used as anticancer drugs in the clinical setting.
Keywords: Natural compound, Cucurbitacins, Anticancer
Abbreviations:
TCH, Traditional Chinese herbs; STAT3, Signal transducer and activator of transcription 3; JAK, Janus kinase;
Bcl-2, B-cell lymphoma 2; ROS, Reactive oxygen species; MAPK, Mitogen-activated protein kinase; ERK,
Extracellular signal-regulated kinase; MAPK, Mitogen-activated protein kinase; NF-κB, Nuclear factor
kappa-light-chain-enhancer of activated B cells; PI3K, Phosphoinositide 3-kinase; AKT, Protein kinase B; mTOR,
Mammalian target of rapamycin; LC3, Light chain 3; p-STAT3, Phosphorylated STAT3; NF2, Neurofibromatosis
type 2.
Competing interests:
The authors declare that there is no conflict of interests regarding the publication of this paper.
Citation:
Jing Liang, Dan Chen. Advances in research on the anticancer mechanism of the natural compound cucurbitacin
from Cucurbitaceae plants: a review. Traditional Medicine Research 2019, 4(2): 68-81.
Executive Editor: Cui-Hong Zhu.
Submitted: 20 September 2018, Accepted: 16 November 2018, Online: 17 December 2018.

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Background
The aggressiveness of various cancers and progressive
tumor resistance and side effects of currently available
chemotherapeutic drugs are the main concerns
associated with cancer treatments used worldwide.
Natural compounds extracted from traditional Chinese
herbs (TCH) exert obvious anticancer effects against
various cancers and thus are new potential anticancer
agents. Increasing number of studies have shown that
cucurbitacins, which are highly unsaturated tetracyclic
triterpenoids produced mainly by plants belonging to
Cucurbitaceae family [1], can be administered in
combination with various chemotherapeutic drugs to
reduce tumor resistance and enhance the efficacy of
these drugs [2-4]. Although most cucurbitacins have a
similar four-ring scaffold structure, they show a
diversity in substituents (Figure 1). Several types of
cucurbitacins are available, of which cucurbitacins B
and E are the main cucurbitacin types [5]. Other
cucurbitacin types are produced through enzymatic
reactions under certain environmental conditions [6].
Cucurbitacins are present in some TCH such as
Gualou (Fructus Trichosanthis), Tianhuafen (Radix
Trichosanthis), and Tianguadi (Pedicellus Melo). An
ancient book named Shennong Bencao Jing (1602
A.D., Donghan Dynasty of China) has reported that
TCH Tianguadi (Pedicellus Melo) and the dried fruit
stalk of Cucumis melo L. have been used for treating
jaundice because components present in these herbs
induce vomiting and aid in expelling phlegm. In the
early 1970s, cucurbitacins B and E were isolated from
Tianguadi (Pedicellus Melo) [7]. Some researchers
have shown that cucurbitacins have hepatoprotective,
anti-inflammatory, antidiabetic, and anticancer
properties [8-10]. Cucurbitacin capsule (approval
number: Z20090820), a Chinese patented medication,
are used for treating chronic hepatitis and primary
hepatocellular carcinoma because of their ability to
induce detoxification, reduce fever, and remove
dampness and yellowing.
Recent studies have focused on the anticancer
effects of cucurbitacins, including cucurbitacins B, E,
D, and I, which are the most common cucurbitacin
derivatives isolated from Cucurbitaceae plants. Many
in vitro studies have shown that cucurbitacins inhibit
cell proliferation, migration, and invasion and induce
G2/M phase cell cycle arrest, autophagy, and apoptosis
through different molecular mechanisms in various
tumor cells [11, 12]. In addition, animal experiments
have shown that cucurbitacins significantly inhibit
tumor growth and metastasis in vivo [1, 13-15],
indicating that these compounds exert a wide range of
anticancer effects. In this review, we have discussed
the advances in research on the anticancer mechanisms
of cucurbitacins.
Anticancer mechanisms of cucurbitacins
Cucurbitacins induce the apoptosis of cancer cells
through various mechanisms
Apoptosis and cell proliferation are the fundamental
mechanisms for maintaining a dynamic balance in a
number of cells in the body. Cancer cells are
characterized by inhibition of apoptosis, which induces
their unlimited proliferation. Therefore, induction of
cancer cell apoptosis by using various treatments is an
important strategy for anticancer therapy.
Cucurbitacins induce apoptosis of various cancer cells
through different pathways (Figure 2). The subsequent
subsections discuss mechanisms through which
cucurbitacins promote cancer cell apoptosis.
STAT3 signaling pathway. Signal transducer and
activator of transcription 3 (STAT3) is one of the most
important member of the STAT family that mediates
the JAK (Janus kinase)/STAT3 signaling pathway and
is closely associated with tumor development and
metastasis [16]. STAT3 overexpression promotes
cancer cell proliferation and migration and inhibits
cancer cell apoptosis. Recent studies have shown that
STAT3 is involved in the resistance of tumor cells to
chemotherapeutic drugs [17-19]. Several studies
performed over the last few years have reported the
effect of cucurbitacins on the STAT3 signaling
pathway, which is considered to be a selective inhibitor
of the JAK/STAT3 pathway.
Liu et al. reported that cucurbitacin B reduces the
phosphorylation of STAT3 and its downstream targets,
including cyclin B1 and BCL-2 (B-cell lymphoma 2),
in human laryngeal Hep-2 cells [20]. In breast cancer
cells, cucurbitacin B inhibits STAT3 phosphorylation
in a time- and dose-dependent manner. However, Kin
et al. reported that cucurbitacin B inhibits ERK
(Extracellular signal-regulated kinase) 1/2
phosphorylation before STAT3 phosphorylation in
leukemia cells, indicating that STAT3 is not the only
target of cucurbitacin B [21]. Cucurbitacin I exerts
antiproliferative effects by inhibiting STAT3 signaling
in breast cancer, glioma, squamous cell carcinoma of
the head and neck, and lung cancer cells [22, 23].
Moreover, cucurbitacin I inhibits tumor angiogenesis
in breast cancer MDA-MB-468 cells by decreasing
STAT3 phosphorylation [24]. In lung cancer A549
cells, cucurbitacin I induces apoptosis through a
JAK/STAT3-dependent pathway [25]. In mice
inoculated with five human osteosarcoma cell lines,
namely, 143B, HOS, MG63, SAOS-2, and HUO9,
cucurbitacin I inhibits tumor growth by inactivating
STAT3, thus improving the survival of these mice [26].
Michelle et al. suggested that cucurbitacin I is highly
selective for the JAK/STAT3 pathway and does not
inhibit other tumor survival pathways [22]. However,
another study reported that cucurbitacin I promotes the
apoptosis of gastric cancer cells by inducing reactive
oxygen species (ROS) production and not by targeting
STAT3 [14]. Cucurbitacin D inhibits the nuclear
translocation and transcriptional activity of STAT3 in
breast cancer MCF7, SKBR3, and MDA-MB-231 cells
[4, 27]. Cucurbitacin E induces the apoptosis of

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pancreatic cancer cells through the STAT3 signaling
pathway [28]. Graness et al. reported that
cucurbitacins exert anticancer effects not by increasing
STAT3 activity but by increasing ROS and antioxidant
levels, which promote cell death [29].
MAPK signaling pathway. MAPK
(Mitogen-activated protein kinase) signaling pathway
is an important pathway involved in cell proliferation,
differentiation, and apoptosis. p38, ERK and JNK
(c-Jun N-terminal kinases), are the important members
of the MAPK family [30]. Many studies have shown
that various cucurbitacins induce apoptosis of cancer
cells through the MAPK signaling pathway.
Cucurbitacin B induces the apoptosis of osteosarcoma
U-2 cells, lung cancer A549 cells, and human
neuroblastoma SH-SY5Y cells by inhibiting the
activation of JNK, ERK1/2, and p38 in a
dose-dependent manner [31-33]. Cucurbitacin E
promotes the apoptosis of triple-negative breast cancer
cells by increasing JNK activation and inhibiting ERK
activation [34]. Deng et al. found that low
concentrations of cucurbitacin I induce cell cycle arrest
in and apoptosis of gastric cancer cells by activating
JNK, p38, and MAPK signaling and by increasing
GSH/GSSG ratio and GADD45α expression, which
forms a positive feedback loop and independently
regulates p53 gene expression [14]. However, a few
studies have reported that cucurbitacin D inhibits the
MAPK signaling pathway, which should be explored
further.
NF-κB pathway. NF-κB (Nuclear factor
kappa-light-chain-enhancer of activated B cells) family
includes five proteins, namely, RelA, RelB, Rel,
NF-κB1, and NF-κB2. NF-κB is a dimeric protein
comprising p65 and p50 subunits, and sustained
NF-κB activation promotes tumor cell proliferation
and inflammation [35]. Ku et al. found that
cucurbitacin D increases the levels of NF-κB in the
cytoplasm and inhibits the nuclear translocation of
phosphorylated NF-κB to induce apoptosis.
Cucurbitacin D also induces the apoptosis of
doxorubicin-resistant breast cancer cells [4]. Ding et al.
found that cucurbitacin D induces apoptosis by
inhibiting intracellular proteasome activity and by
reducing NF-κB nuclear translocation and BCL-2 and
BCL-XL expression [36]. Treatment of glioblastoma
cells with cucurbitacin I activates the NF-κB pathway
by inducing the phosphorylation and nuclear
translocation of the NF-κB p65 subunit, which occurs
before the inhibition of STAT3 [37].
Figure 1 Structures of various cucurbitacin derivatives
(A) The general structure of cucurbitacins. (B) The structure of cucurbitacin B. (C) The structure of cucurbitacin
D. (D) The structure of cucurbitacin E. (E) The structure of cucurbitacin I.

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PI3K/AKT pathway. Many recent studies have shown
that the activation of the PI3K/AKT signaling pathway
plays an important role in many biochemical processes,
including the proliferation and survival of breast
cancer, cervical cancer, human osteosarcoma, and
other cancer cells [38]. Wang et al. found that
cucurbitacin E inhibits the growth of human
osteosarcoma cells both in vitro and in vivo through the
PI3K/AKT/mTOR signaling pathway [39]. Moreover,
cucurbitacin E reduces phosphorylated AKT(Protein
kinase B) and total AKT levels in triple-negative breast
cancer cells [34]. Cucurbitacin D also inhibits the
PI3K/AKT signaling pathway in cervical and gastric
cancer cells by decreasing PI3K and p-AKT (Ser473)
levels [15, 40]. Cucurbitacin I induces the apoptosis of
A549 cells by inhibiting the activation of ERK and
phosphorylation of its downstream proteins mTOR
(Mechanistic target of rapamycin) and STAT3;
however, it does not inhibit the PI3K/AKT pathway
[25].
Other pathways. Some studies have reported that
cucurbitacins promote cancer cell apoptosis through
other mechanisms besides those mentioned above. A
study showed that cucurbitacin B inhibits breast cancer
growth both in vivo and in vitro by inhibiting Wnt and
HER2/integrin signaling [41]. Duangmano et al.
suggested that cucurbitacin B promotes the apoptosis
of human breast cancer cells by disrupting microtubule
networks [42]. Cucurbitacins also induce the apoptosis
of human T cell leukemia Jurkat cells by disrupting
cellular actin mechanics and by activating its key
regulator cofilin [43]. Cucurbitacin B increases the
production of intracellular ROS in leukemia K562
cells, thus inducing their apoptosis [44]. It also induces
the apoptosis of colon cancer SW480 cells through a
STAT3-independent but an ROS-dependent
mechanism [45]. Cucurbitacin E induces the apoptosis
of cervical cancer HeLa and CaSki cells by
upregulating the expression of death receptor 5 [46].
Cucurbitacin I promotes the apoptosis of liver cancer
HepG2 cells by activating p53 and its downstream
targets. Cucurbitacin D effectively induces the
apoptosis of gastric cancer cells by activating the
inducible nitric oxide synthase pathway [40]. These
findings indicate that cucurbitacins use variable and
complex mechanisms to induce the apoptosis of cancer
cells.
Cucurbitacins induce autophagy in tumor cells
through various mechanisms
Figure 2: Signaling pathways involved in cucurbitacin-induced apoptosis
STAT3, Signal transducer and activator of transcription 3; JAK, Janus kinase; Bcl-2, B-cell lymphoma 2; ROS,
Reactive oxygen species; Erk1/2, Extracellular signal-regulated kinase1/2; MAPK, Mitogen-activated protein
kinase; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, Phosphoinositide 3-kinase;
Akt, Protein kinase B; mTOC1, mTOR complex 1.

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Autophagy is an important process for maintaining
homeostasis in eukaryotic cells. Autophagy signaling
pathways are activated under certain circumstances to
degrade damaged macromolecular substances and to
provide energy for cell survival. In cancer therapy,
autophagy plays a dual role, such as the inhibition of
autophagy promotes cancer cell death, whereas
excessive autophagy leads to autophagic cell death [47,
48]. Studies involving various cancer cell lines have
shown that cucurbitacins B, D, E, and I induce the
production of ROS, which play an important role in
mediating DNA damage and in inducing protective
autophagy [44, 49-54]. Liu et al. reported that
cucurbitacin B inhibits CIP2A/PP2A/mTORC1
signaling axis-induced autophagy in cisplatin-resistant
human gastric cancer SGC7901/DDP cells [55]. In
vitro treatment of leukemia cells with cucurbitacin B
induces autophagy as a survival response; however,
specific mechanisms underlying this are unclear[43].
Cucurbitacin E induces autophagy by downregulating
the mTORC1 signaling pathway and by upregulating
AMPK activity [56]. Microtubule-associated protein
light chain 3 (LC3) is the key factor in autophagosome
formation. Cucurbitacins D, E, and I induce autophagy
by upregulating the LC3 gene expression in human
gastric cancer cells, with the effect of cucurbitacin I
being significantly higher than those of cucurbitacins
D and E [57]. Ni et al. found that cucurbitacin I
induces damage-associated autophagy in gastric cancer
A549 cells by inhibiting the ERK/mTOR/STAT3
signaling pathway [25].
Competitive mechanisms of cucurbitacin-induced
autophagy and apoptosis
Most studies on cucurbitacins have focused on their
effect on promoting cancer cell apoptosis. The ability
cucurbitacins to inhibit cell proliferation does not
depend only on the STAT3 pathway. Many studies
have reported that the morphological and biochemical
features of cucurbitacin-induced apoptosis of human
cancer cells are not apparent and that cell death is
induced by ROS-mediated autophagy in most
cucurbitacin-treated cancer cells. In recent years,
cucurbitacin-induced autophagy has attracted
considerable amount of attention; however,
mechanisms underlying cucurbitacin-induced
autophagy are not completely understood. Research
has shown that cucurbitacin-induced autophagy
competes with apoptotic signaling to limit the effect of
apoptosis [58]. Cucurbitacins induce cell-protective
autophagy and other competing apoptotic mechanisms
or increase apoptotic resistance. Some studies have
shown that cucurbitacins induce autophagy based on
damaged cellular morphology. Moreover, the damaged
cellular morphology that induces pro-death autophagy
differs from the damaged cellular morphology that
induces apoptosis. We believe that cucurbitacins may
act on signaling pathways that are common between
apoptosis and autophagy but may show a different
order of induction of both these processes.
Furthermore, apoptosis and autophagy may activate or
inhibit one another after cucurbitacin treatment.
Therefore, additional studies should be performed to
determine the complex relationship between
cucurbitacin-induced autophagy and apoptosis.
Cucurbitacins induce cytoskeletal destruction
Cucurbitacins induce morphological changes in cancer
cells within a short period. Changes in actin filaments
and microtubules play an important role in cancer cell
proliferation, which is an important target of natural
compounds used in cancer treatment [59]. Wang et al.
compared cucurbitacins B, E, and I with vincristine
and colchicine and showed that the cucurbitacins
interacted with the cytoskeleton and actin filaments to
induce cell cycle arrest. In addition, cucurbitacins
interfered with microtubule structure, thus affecting
cell mitosis [60]. Cucurbitacin E disrupts the
cytoskeletal structure and inhibits the proliferation of
prostate cancer cells [61]. Cucurbitacin B covalently
binds to cofilin, thus increasing actin depolymerization.
However, some studies have shown that cucurbitacins
do not directly bind to cofilin but inhibit the regulation
of cofilin phosphorylation kinase to increase actin
depolymerization and stimulate Rho/ROCK pathway
to induce actin and phosphorylated myosin II
co-aggregation [62, 63]. However, Zhang et al.
suggested that cucurbitacin B induces the actin
aggregation through Gα13/RhoA/PKA/VASP signaling
pathway [64]. Although several studies have attempted
to determine mechanisms underlying
cucurbitacin-induced cytoskeletal destruction, these
studies have provided different results. Therefore,
specific mechanisms underlying cucurbitacin- induced
cytoskeletal destruction are still unclear and should be
determined by performing additional studies.
Cucurbitacins induce cell cycle arrest in cancer
cells
A cell cycle involves a series of events in a cell from
mitosis to the end of the next division. The length of a
cell cycle reflects the state of a cell and is a cyclical
process of cell material accumulation and cell division.
Cancerous cells often show abnormal division cycles.
Many studies have shown that cucurbitacins induce
cell cycle arrest at different stages depending on the
cell type. Cucurbitacin B arrests the cell cycle in the S
phase in BEL-7402, HL60, and U937 cells and in the
G2/M phase in Panc-1, MiaPaCa-2, K562, SW480,
and Hep-2 cells [6]. In pancreatic cancer cells,
cucurbitacin B may induce cell cycle arrest in the
G2/M phase by inhibiting JAK2, STAT3, and STAT5
activation; increasing p21 level; and decreasing cyclin
A and cyclin B1 expression [65]. In human
hepatocellular carcinoma BEL-7402 cells, cucurbitacin
B-induced cell cycle arrest in the S phase is associated
with the inhibition of cyclin D1 and cyclin-dependent
kinase-1 expression but is not associated with STAT3
phosphorylation [66]. Most studies have suggested that
cells arrested in the G2/M phase of the cell cycle are

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tetraploid cells that have undergone nuclear division
but are unable to complete cytokinesis. Drugs that
affect the microfilament skeleton induce various
degrees of cell cycle arrest; therefore, cell cycle arrest
induced by cucurbitacin B is most likely to be a
consequence of damage to the microfilament skeleton
[60]. Multiple types of leukemia cells treated with
cucurbitacin B show significant cell cycle arrest in the
S phase [67]. Kong et al. compared 12 natural drugs,
including cucurbitacins B, E, and I, in four cancer cell
lines and found that cucurbitacin E significantly
reduced the viability of MAD-MB-468 and SW527
cells by regulating cyclin D1 and cyclin B expression,
inhibiting phosphorylated STAT3 (p-STAT3), and
activating p53 and p21, eventually leading to cell cycle
arrest in the G2/M phase [34, 68]. Cucurbitacin D
inhibits the proliferation of endometrial cancer and
ovarian cancer cells and increased the ratio of these
cells in the sub-G0/G1 and G2/M phases of the cell
cycle [69]. No FDA-approved drugs are available for
treating neurofibromatosis type 2 (NF2)-associated
schwannomas and meningiomas. Spear et al. found
that cucurbitacin D exerts anticancer effects on
NF2-deficient mouse schwannoma Sch10545 cells and
human benign meningioma Ben-Men-1 cells by
increasing the number of cells in the G2/M phase and
inhibiting the proliferation of these cells, suggesting its
potential as a therapeutic agent for treating these
diseases [70]. Jafargholizadeh et al. found that
treatment of human gastric cancer AGS cells with
cucurbitacins D, E, and I induces cell cycle arrest in
the sub-G1 phase, eventually leading to cell death [57].
These studies indicate that cucurbitacins play an
important role in cell cycle arrest and that the effect of
cucurbitacins on cell cycle arrest differs between
different cell types.
Combination treatment with cucurbitacins and
chemotherapeutic drugs
The aggressiveness of various cancers and tumor
resistance and side effects of currently available
chemotherapeutic drugs are serious concerns
associated with cancer treatment. Cucurbitacins, which
are natural compounds, exert obvious antiproliferative
effects on various tumor cells, indicating their potential
as anticancer agents. STAT3 is associated with
resistance against anticancer drugs and is highly
expressed in many drug-resistant cancer cells. Because
cucurbitacins mainly target STAT3, several studies
have examined the combination of cucurbitacins with
various chemotherapeutic drugs and have shown that
cucurbitacins reduce the resistance against and
enhance the efficacy of these drugs. The findings of
these studies suggest that cucurbitacins are potential
candidates for use in combination therapy with clinical
anticancer drugs.
Cucurbitacins and chemotherapeutic drugs
synergistically exert anticancer effects. Tang et al.
found that cucurbitacin B synergistically increases the
antitumor activity of doxorubicin by blocking the
STAT3 pathway [2]. Cucurbitacin B also enhances the
anticancer effect of imatinib mesylate by inhibiting
matrix metalloproteinase-2 expression in MCF7 and
SW480 tumor cells [71]. The combination of
cucurbitacin B with gefitinib induces cell cycle arrest
and apoptosis in human colorectal cancer cells through
the EGFR and JAK/STAT pathways [3]. Lee et al.
showed that treatment with low doses of cucurbitacin
B and methotrexate synergistically inhibit the AKT and
mTOR signaling pathways in human osteosarcoma
cells both in vivo and in vitro [72]. El-Senduny et al.
treated ovarian cancer A2780 cells and
cisplatin-resistant A2780CP cells with a combination
of cucurbitacin B and cisplatin or pretreated these cells
with cucurbitacin B, followed by treatment with
cisplatin. Results of contrast analysis performed in this
study showed that the combination of cisplatin and
cucurbitacin B decreased the levels of dual specificity
tyrosine phosphorylation regulated kinase 1B,
phosphorylated ERK1/2, and p-STAT3 and increased
the level of ROS, thus significantly enhancing the
effect of cisplatin on the ovarian cancer cells [73].
Moreover, cucurbitacin B synergistically exerts
antiproliferative effects along with cisplatin on
cutaneous squamous cell carcinoma cells [74] and
enhances the effect of arsenic trioxide-induced
apoptosis by inhibiting STAT3 phosphorylation in
lymphoma Ramos cells. In addition, the combination
of cucurbitacin B and arsenic trioxide does not exert
any proapoptotic effects on normal lymphocytes,
indicating that this combination is non-toxic against
normal blood cells. Experiments involving an in vivo
nude mouse lymphoma model have further confirmed
this synergistic effect of cucurbitacin B and arsenic
trioxide [75]. Ku et al. found that cucurbitacin D
promotes the apoptosis of doxorubicin-resistant breast
cancer cells through STAT3 and NF-κB [4]. Chang et
al. found that cucurbitacin I increases the sensitivity of
medulloblastoma-derived cancer stem cells to
apoptosis induced by chemotherapeutic drugs targeting
STAT3 [76].
Cucurbitacins can be safely used in combination
with chemotherapeutic drugs. Myelosuppression and
hepatorenal toxicity are the common side effects of
chemotherapy. Ahmed et al. showed that the
combination of cucurbitacin B with chemotherapeutic
drugs did not increase toxicity in immunosuppressed
mice undergoing orthotopic transplantation of breast
cancer. Neurosensory and neuromotor toxicities are
common in patients treated with docetaxel and other
taxanes. However, it was found that treatment with the
combination of docetaxel with cucurbitacin B was
associated with lower neurotoxicity than treatment
with docetaxel alone. These findings suggest that
cucurbitacins exert protective effects against
docetaxel-induced neurotoxicity; however, specific
mechanisms underlying this effect of cucurbitacins are
unknown [77]. Previous studies have reported that
cucurbitacin E can be used in combination with
doxorubicin for treating ovarian cancer and enhances

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the efficacy of doxorubicin. An in vitro study has
shown that cucurbitacin E increases doxorubicin level
in M5076 ovarian sarcoma cells by suppressing
doxorubicin efflux [78]. Sadzuka et al. found that
cucurbitacin E can be used in combination with
doxorubicin for treating ovarian cancer to enhance the
efficacy of doxorubicin without increasing its side
effects. As mentioned previously, cucurbitacin E
inhibits the efflux of doxorubicin from the M5076
ovarian sarcoma cells, thus significantly increasing its
concentration in tumor cells and reducing its
concentration in normal cells. Tumor cells and normal
cells show differences in membrane transporter
expression; thus, the differences in the role of
cucurbitacin E between tumor and normal tissues may
be because of differences in the expression of
multidrug resistance-associated proteins between these
tissues [36].
Conclusion
Cucurbitacins are natural compounds with various
pharmacological activities, and their antitumor effects
have received increasing attention. These compounds
can
prevent the proliferation of different tumor cells by
inducing apoptosis, cell cycle arrest, autophagy, and
cytoskeletal disruption (Table 1). Although many
studies have reported the antitumor activity of
cucurbitacins, mechanisms underlying this activity of
cucurbitacins are unclear. Cucurbitacins exert
anticancer effects both in vivo and in vitro through
multiple targets, indicating their enormous anticancer
potential. The combination of cucurbitacins with
chemotherapeutic drugs also exerts strong synergistic
anticancer effects. However, determination of the
antitumor effects of cucurbitacins is challenging
because of the complex mechanism of tumorigenesis.
Therefore, additional in-depth studies on cucurbitacins
should be performed to confirm their potential as drug
candidates for cancer treatment in the clinical setting.
Table1: Cucurbitacins inhibits proliferation of different cell lines
Cucurbitacins Cancer cell lines Mechanism
B Human leukemia cells: CCRF-CEM, K562,
MOLT-4, RPMI-8226, SR, and Jurkat
DNA damage induction, G2/M phase cell cycle
arrest, autophagy induction, actin cytoskeleton
alteration, and apoptosis induction [21, 43, 44]
Breast cancer cells: MDA-MB-231, MCF7,
ZR-75-1, T47D, BT474, MDA-MB-453,
SKBR-3, HCC1937, MDA-MB-436, and 4T-1
Integrin-HER2 signaling inhibition, DNA damage
and autophagy induction, microtubule
polymerization disruption, G2/M phase cell cycle
arrest, telomerase inhibition, and apoptosis induction
[8, 41, 42, 49, 79, 80]
Colon cancer cell lines: SW480 and HCT-116 Cell cycle inhibition and apoptosis induction [3, 71]
Hepatic carcinoma cell lines: BEL-740 and
HepG2 cells
Protective autophagy induction [54], apoptosis
induction, and S phase cell cycle arrest [66, 81]
Acute leukemia cell lines: RCH, Reh, BALL-1,
MD901, LY4, HL60, U937, THP1, K562, and
NB4
Cell cycle arrest and actin cytoskeleton alteration
[67]
Prostate cancer cell lines: PC-3 and LNCaP Apoptosis induction [82]
Pancreatic cancer cell lines: ASPC-1, BxPC-3,
CFPAC-1, HPAC, Panc-1, and MiaPaCa-2
G2/M phase cell cycle arrest and apoptosis induction
[65, 83]
Osteosarcoma cell lines: U-2OS, G292, MG-63,
HT-161, HOS, SAOS-2, and SJSA
Apoptosis induction [31, 72]
Non-small-cell lung cancer cell lines: A549,
H1792, H1650, and H1975
Apoptosis induction [8, 84]
Throat cancer cell line: Hep-2 Cell cycle arrest and apoptosis induction [20, 85]
Melanoma cell lines: Human A375 and murine
B16F10
Actin aggregation induction [64]
Glioblastoma multiforme cell lines:
DBTRG‐05MG, U251MG, U118MG, U87MG,
T98G, and LN229
Invasive behavior inhibition, apoptosis induction
[86], and cytoskeletal damage [87]
Cutaneous squamous cell carcinoma cell lines:
SRB1, SRB12, SCC13, and Colo16
G2/M phase cell cycle arrest and cell migration
inhibition [74]
Cervical cancer cell line: HeLa G2/M phase cell cycle arrest and apoptosis induction
[88]
Neuroblastoma cell line: SH‑SY5Y Apoptosis induction [32]
Lymphoma cell line: Ramos Apoptosis induction [75]

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D Breast cancer cells lines: MCF7 and MDA-MB-231 Cell cycle arrest and apoptosis induction [4]
T cell leukemia cell lines: MT-1, MT-2, MT-4, Hut102,
Hut78, and Jurkat
Apoptosis and autophagy induction [52, 89]
Hepatic carcinoma cell line: Hep3B Apoptosis induction through caspase-3 and JNK
phosphorylation [90]
Colon cancer cell lines: HT29, Colo320, and Caco2 Apoptosis induction [91]
Lung cancer cell lines: A549 and AGS Apoptosis induction and cell cycle arrest [57, 91]
Cervical cancer cell lines: HeLa and SiHa Apoptosis induction and G1/S phase cell cycle
arrest [15]
NF2-deficient schwannoma cell line: Sch10545 Apoptosis induction and cell cycle arrest [70]
Gastric cancer cell lines: AGS, SNU1, and Hs746T Apoptosis induction [40]
Endometrial cancer cell lines: HHUA and HEC59 Apoptosis induction and cell cycle arrest [69]
Ovarian cancer cell lines: SK-OV-3, OVCAR-3, and
TOV-112D
Apoptosis induction and cell cycle arrest [69]
E Breast cancer cell lines: Bcap37, MDA-MB-231,
MDA-MB-468, and SW527
G2/M phase cell cycle arrest and apoptosis
induction [34, 92]
Human leukemia cell line: U937 Actin depolymerization [93]
Lung cancer cell lines: A549 and 95D Caspase-dependent apoptosis induction and
protective autophagy induction [94, 95]
Brain malignant glioma cell line: GBM 8401 G2/M phase cell cycle arrest [96]
Oral squamous cell carcinoma cell line: SAS Cell death and apoptosis induction [97]
Cervical cancer cell lines: HeLa and CaSki Apoptosis induction [46]
Prostate cancer cell lines: LNCaP, PC-3, and DU145 Apoptosis induction [98] and actin and vimentin
cytoskeleton disruption [61]
Pancreatic cancer cell line: Panc-1 G2/M phase cell cycle arrest and apoptosis
induction [28]
Ovarian cancer cell lines: ES-2 and M5076 Apoptosis induction and cell cycle arrest [36, 99]
Bladder cancer cell line: T24 G2/M phase cell cycle arrest and apoptosis
induction [68]
Hepatic carcinoma cell lines: HepG2 and BEL-7402 In vitro cytotoxicity induction [100]
I Breast cancer cell lines: MDA-MB-468,
MDA-MB-231, T-47D, MCF7, BT-474, and HCC1419
Cell viability, proliferation, adhesion, migration,
and tube formation inhibition [24] and cell motility
inhibition [101]
Colon cancer cell lines: SW480, CT-26, and HCT-116 Apoptosis induction [8]
Lung cancer cell lines: NCI-H460 and A549 Apoptosis induction and actin filament disruption
[102]
Gastric cancer cell line: AGS Sub-G1 phase [57] and G2/M phase cell cycle
arrest and apoptosis induction [14]
Glioblastoma multiforme cell lines: GBM, U251, and
A172
G2/M cell cycle arrest and apoptosis induction
[103]
Nasopharyngeal carcinoma cell lines: HK1 and CNE-2 Apoptosis induction [23]
B cell leukemia cell lines: BJAB, I-83, NALM-6, and
primary CLL
Apoptosis induction and cell cycle arrest [104]
Malignant glioma cell lines: T98G and U251 Protective autophagy induction [53]
Nasopharyngeal carcinoma cell lines: HK1 and CNE-2 Apoptosis induction [23]

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