Cytotoxic activities of cucurbitane-type triterpene glycosides
The WHO says that annual cases of cancer will increase from 14 million in 2012 to 22 million in the next two decades. Cancer is the second cause of death in the world; in 2015, it caused 8.8 million deaths. On the other hand, it is necessary to consider that 70% of the total deaths due to this disease occur in developing countries, who have the least resources to acquire the drugs of choice for the treatment of this disease. Although there are treatments and these are effective, there are currently cases of resistance to drugs used to treat this disease, which has led to the search for new sources of drugs or compounds effective against the cancer being active; plants are the possible sources to achieve this. Cucurbitaceae is a family of plants widely distributed on the planet which has been used traditionally for the treatment of this disease and from they have been isolated different cucurbitanes. These compounds possess a wide biological activity, antidiabetic, anti-inflammatory, hepatoprotective, or cytotoxic and antitumoral effects. The aim of this review is to present 51 cucurbitacin compounds and 2 with different structures isolated from Cucurbitaceae plants with cytotoxic or antitumoral activity.
- natural product
Cancer is an abnormal growth of cells, which begin to divide without stopping and can form solid tumors. Cancer is a collection of more than 100 different diseases with genetic changes, which can be inherited or be caused by environmental exposure to chemicals, tobacco smoke, or radiation, such as UV rays from the sun.
Cancer is the second leading cause of death in the US and is responsible for approximately 1 out of every 4 deaths. Globally, nearly 1 in 6 deaths is due to cancer. Approximately, 70% of deaths from cancer occur in low- and middle-income countries. There were 14.1 million new cancer cases, 8.2 million cancer deaths, and 32.6 million people living with cancer (within 5 years of diagnosis) in 2012 worldwide, based on World Health Organization (WHO) estimates. A total of 57% (8 million) of new cancer cases, 65% (5.3 million) of cancer deaths, and 48% (15.6 million) of 5-year prevalent cancer cases occurred in less-developed regions [1, 2].
The most common treatments for cancer are surgery, chemotherapy, and radiation therapy, and in many cases, they are used in combination . These treatments can be effective but can cause side effects, such as anemia, appetite loss, fatigue, and alopecia .
1.1 Generalities of the Cucurbitaceae family
Plants are an important source of compounds currently used in cancer chemotherapy. The Cucurbitaceae family, also called cucurbits, contains 120 genera with 825 species that are widely distributed in tropical and temperate regions , and those with edible fruits were the first cultivated plants in Europe and America. Many species of the Cucurbitaceae family are used as human food . Most of the species in this family are annual vines, and some are lianas, thorny shrubs, or trees. The most important genera of this family are
1.2 Cucurbitanes of the Cucurbitaceae family with cytotoxic effects
Some cucurbitanes have been isolated from different species of the Cucurbitaceae family. These compounds exhibit an extensive range of biological actions, specifically antidiabetic, anti-inflammatory, cytotoxic, hepatoprotective, cardiovascular, and antiparasitic effects .
Cucurbitacins are characteristic compounds in many species of cucurbits. These compounds are tetracyclic triterpenes arising from a rearrangement of the protostane cation and are unsaturated and polyfunctional oxygenated compounds and occur most often as glycosides. They are particularly toxic and bitter chemicals, and their cytotoxicity contributes to their toxicity . Cucurbitanes are found in many plants.
The most significant mechanisms of the apoptotic effects of cucurbitacins are their ability to modify the mitochondrial transmembrane potential and transcriptional activity via nuclear factors or genes and their ability to activate or inhibit pro- or antiapoptotic proteins.
Similar to other plant-derived compounds, cucurbitacins exert toxic effects in different cancer cell lines by inducing apoptosis. The main mechanism of this induction is the ability to modify the mitochondrial transmembrane potential .
Therefore, some compounds obtained from Cucurbitaceae could be useful scaffolds for developing new drugs. We consider it necessary to review the main chemicals from this genus with potential anticancer activity.
2. Cucurbitacins tetracyclic triterpenoids
Cucurbitacins are primarily tetracyclic triterpenoids (Figure 1) that compose a class of biochemical compounds contained in plants of the family Cucurbitaceae, which include the Thai medicinal plants
2.1 Cucurbitacin B (
Cucurbitacin B (CuB) is an oxygenated tetracyclic triterpenoid compound (
CuB potently suppressed the growth of four types of NSCLC cells (H1299, A549, HCC-827, and H661), inhibiting the proliferation of all the cell lines with IC50 values between 0.05 and 0.130 μM. The mean tumor volume at the end of the study in CuB-treated mice was 200 ± 111 mm3, compared to 684 ± 321 mm3 in the control group (average reduction of 70% in tumor volume (p < 0.05). No visible sign of toxicity was observed in CuB-treated mice . CuB could suppress human NSCLC cell growth in vitro through its effects on the PI3Kinase and MAPK pathways, which lead to programmed cell death induction, as well as inhibition of cell migration and cell invasion . Additionally, CuB induces cell cycle arrest in A-549 cells and causes DNA double strand breaks. It also produces DNA damage and G2/M phase arrest; this damage could be due to an increase in reactive oxygen species (ROS) formation .
The cytotoxic effect of CuB was tested on HeLa and U2OS cells, and the IC50 values were 12.2 and 17.07 μM, respectively. The inhibition of tubulin polymerization in vitro was observed with an IC50 > 1 mM . CuB from the leaves of Tunisian
2.2 23,24-Dihydrocucurbitacin B (DHCB) (
DHCB inhibited the viability of human cervical cancer cell lines with an IC50 of 40–60 μM, but its cytotoxic effects were less pronounced in normal epithelial fr2 and HerEpiC cells, where the IC50 was 125 μM. The underlying mechanisms were studied, and the results showed that DHCB induced apoptosis in HeLa cells and caused ROS-mediated shifts in the ΔΨm. Additionally, DHCB caused cell cycle arrest in HeLa cells at the G2/M checkpoint. The phosphoinositide 3 kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) cascade may play an important role in cancer tumorigenesis and progression and resistance to chemotherapy. The results indicated that DHCB decreased the expression of important proteins in the PI3K/Akt/mTOR cascade .
2.3 23,24-Dihydrocucurbitacin F (DHCF) (
2.4 Cucurbitacin E (4′)
The inhibition of breast cancer metastasis in mouse models by CuE was reported. To evaluate the effect of CuE on the proliferation and apoptosis of inoculated 4T1 and MDA-MB231 cells in vivo, the expression of proliferating cell nuclear antigen (PCNA) and cleaved caspase-3 was tested by immunohistochemical analysis . CuE targets the dissemination of breast cancer cells from the primary tumor but not the outgrowth of established micrometastases in target organs (lung, liver, between others). CuE exerts no significant effect on tumor cell apoptosis or proliferation in vivo .
CuE demonstrated cytotoxic activity against human oral squamous cell carcinoma SAS cells with an IC50 of 3.69 μM and induced the apoptosis of SAS cells after 24 h of treatment, but not MRC-5 or HS68 cells, which showed a dose-dependent reduction. Microscopic examination showed that following exposure to CuE (2.5 μM) for 6–24 h, the cells displayed a remarkable change in their morphology, and CuE induced the death of cancer cells .
The inhibitory effect of CuE on the proliferation of Bcap37 and MDA-MB-231 cells was assessed by the MTT assay. Breast cancer cells were treated with various concentrations (0, 0.1, 1, 10, and 100 μM) of CuE or DMSO as a control for 24, 48, and 72 h. The MTT method was then used to determine the number of viable cells. The data indicated that CuE inhibited cell growth in a concentration- and time-dependent manner (ANOVA, p < 0.05). After treatment with 0.1 μM CuE for 24 h, the growth of Bcap37 and MB-231 cells was significantly inhibited. At a CuE concentration of 100 μM, most of the cancer cells detached from the dish .
Additionally, CuE was evaluated on the chondrosarcoma SW 1353 cancer cell line, and the IC50 values indicated higher toxicity in this cell line than in the previously test lines (MTT assay). The amount of CuE that induced a mortality of 50% was calculated after 6, 12, and 24 h of treatment, and the results were 13.55, 12.65, and 9.16 μM, respectively . The cytotoxic effect of CuE was tested on HeLa and U2OS cells, and the IC50 values were 6.43 and 15.07 nM, respectively. The inhibition of tubulin polymerization in vitro had an IC50 of 566.91 nM .
The effects of CuE from
2.5 Cucurbitacin R (5′)
One additional cucurbitacin was discovered in the roots of
2.6 Cucurbitacin I (6′)
CuI, also known as elatericin B or JSI 124, has been isolated from different plants, such as
The cytotoxicity IC50 values of CuI in SW 1353 cells after 6, 12, and 24 h of treatment were 7.93, 8.31, and 5.06 μM, respectively . The cytotoxic activity of CuI against SW-480 human colon cancer cells was tested. In this case, CuI diminished cell proliferation in a concentration-dependent manner and increased apoptosis, enhancing cycle arrest at the G2/M phase .
The cytotoxicity of CuI was tested in HeLa and U2OS cells, and the IC50 values were 44.77 and 23.47 nM, respectively. The inhibition of tubulin polymerization in vitro had an IC50 > 1 mM . The effects of CuI purified from
2.7 Cucurbitacin D (7′)
CuD was evaluated in the chondrosarcoma SW 1353 cancer cell line. Its IC50 values against SW 1353 cells after 6, 12, and 24 h of treatment were 16.48, 13.03, and 13.14 μM, respectively .
The effects of CuD purified from
2.8 Cucurbitacin A (8′)
The antiproliferative effects of Cucurbitacin A (CuA) on A-549 cells were determined by using the MTT assay. This compound exhibited a potent cytotoxic effect on A-549 cells. The assay was carried out at different concentrations of CuA (0, 10, 20, 40, 100, 150, and 200 μM) with incubation for 24 and 48 h. CuA showed inhibitory effects on cell proliferation in a dose- and time-dependent manner. However, the effect of the incubation time was more pronounced at higher doses of the compound. CuA also induced morphological changes in these cells, featuring chromatin condensation, cell shrinkage, and apoptotic body formation. G2/M phase cell cycle collapse was also induced by CuA along with inhibition of the expression levels of m-TOR/PI3K/Akt proteins .
2.9 2 β,3β,16α,20(
R),25-Pentahydroxy-22-oxocucurbita-5-en (RPO) (9’)
This compound is a cucurbitacin isolated from
2.10 Cucurbitaglycosides A (10′) and B (11′)
Phytochemical investigation of the fruits of
2.11 Hemslecin A (12′)
Three cucurbitane triterpenoids were isolated from
3. Cucurbitane-type triterpene glycosides
Two new cucurbitane-type triterpene glycosides, charantagenins D (
|Cancer cell line||IC50 values (μM)|
|A549 lung cancer cell line|
|U87 glioblastoma cell line|
|Hep3B hepatoma carcinoma cell line|
|SKHep1 human hepatoma cell line|
3.1 Momordicin VII (29′)
Several new cucurbitane triterpenoids were isolated from the stems and leaves of
4. Multiflorane-type triterpenes
Multiflorane-type triterpenes (Figure 5), a new class of cucurbitacins, were isolated from seeds of
Three new multiflorane-type triterpenes, 7α-methoxymultiflor-8-ene-3α,29-diol-3-acetate-29-benzoate (
5. Cyclic bisdesmosides
Cyclic bisdesmosides, new compounds analogous to cucurbitacins, share the tetracyclic triterpenoid core but contain carbohydrates to form a bicycle (Figure 6). These compounds were isolated from
Two new cyclic bisdesmosides elucidated as lobatoside L (
|Cancer cell lines||IC50 values (μM)|
|Esophageal squamous carcinoma cell line ECA-109|
|Lung cancer cell line A549|
|Gastric cancer cell line MGC-803|
Tubeimoside I (
The gypenosides (Figure 7) were isolated from
Gypenoside L (
7. Other substances of interest
In addition to the cucurbitacins, other substances isolated from the Cucurbitaceae family have been identified, including proteins isolated from the sarcocarp of
A novel type-1 ribosome-inactivating protein (RIP) designated cucurmosin was isolated from the sarcocarp of
Cucurmosin was tested for its cytotoxicity against human leukemia cells (K562), murine melanoma cells (B16), lung adenocarcinoma cancer cells (A549), and peripheral blood lymphocytes using the standard MTT assay. The IC50 values of cucurmosin were 88.1, 63.4, and 359.3 nM in human leukemia cells (K562), murine melanoma cells (B16), and lung adenocarcinoma cancer cells (A549), respectively, while its IC50 in normal cells (peripheral blood lymphocytes) was higher than 1.4 μM .
Trichosanthin was isolated from the roots of
Tianhua, an extract of
The aim of this review is to present 51 cucurbitacin compounds and two compounds with different structures isolated from Cucurbitaceae plants, their chemical structures, their biological activities, and the mechanisms by which these compounds reduce the proliferation of cancer cells.
Conflict of interest
The authors declare that there is note conflict of interest.