Abstract
Modern treatment strategies provide better overall survival in cancer patients, primarily by controlling tumor growth. However, off-target and systemic toxicity, tumor recurrence, and resistance to therapy are still inadvertent hurdles in current treatment regimens. Similarly, metastasis is another deadly threat to patients suffering from cancer. This has created an urgent demand to come up with new drugs having anti-metastatic potential and minimum side effects. Thus, this study was aimed at exploring the anti-proliferative and anti-metastatic potential of colocynth medicinal plant. Results from MTT assay, morphological visualization of cells and scratch assay indicated a role of ethanol and acetone extracts of fruit pulp of the colocynth plant in inhibiting cell viability, enhancing cell cytotoxicity and preventing cell migration in various cancer cell types, including breast cancer cell lines MCF-7 and MDA-MB-231, and cervical cancer cell line SiHa, subsequently having a low cytotoxic effect on mononuclear PBMC and macrophage J774A cells. Our study in metastatic MDA-MB-231 cells showed that both ethanol and acetone pulp extracts decreased transcript levels of the anti-apoptotic genes BCL2 and BCLXL, and a reverse effect was observed for the pro-apoptotic genes BAX and caspase 3. Additionally, enhanced caspase 3 activity and downregulated BCL2 protein were seen, indicating a role of these extracts in inducing apoptotic activity. Moreover, MDA-MB-231 cells treated with both these extracts demonstrated up-regulation of the epithelial gene keratin 19 and down-regulation of the mesenchymal genes, vimentin, N-cadherin, Zeb1 and Zeb2 compared to control, suggesting a suppressive impact of these extracts in epithelial to mesenchymal transition (EMT). In addition, these extracts inhibited colony and sphere formation with simultaneous reduction in the transcript level of the stemness associated genes, BMI-1 and CD44. It was also found that both the plant extracts exhibited synergistic potential with the chemotherapeutic drug doxorubicin to inhibit cancer viability. Furthermore, GC-MS/MS analysis revealed the presence of certain novel compounds in both the extracts that are responsible for the anti-cancer role of the extracts. Overall, the results of this report suggest, for the first time, that colocynth fruit pulp extracts may block the proliferative as well as metastatic activity of breast cancer cells.
Highlights
Cancer constitutes a group of deadly diseases that is the second leading cause of death worldwide, and largely contributes to the global health economic burden
To test the anticancer potential of colocynth fruit pulp extracts, cell viability was measured by MTT assay
In case of ethanol extract, LC50 values were 142 ± 16, 105 ± 8.3 and 157 ± 4.3 for MDA-MB-231, MCF-7 and SiHa cell lines respectively (Table 1). These values were 140 ± 0.8, 94 ± 6.4 and 121 ± 4.6 respectively. These findings indicated relatively higher efficacy of pulp acetone extract (PAE) in cancer cell lines compared to pulp ethanol extract (PEE)
Summary
Cancer constitutes a group of deadly diseases that is the second leading cause of death worldwide, and largely contributes to the global health economic burden. Breast and cervical cancers are the most frequently diagnosed cancers in females nationwide, accounting for about 1.7 million new cases and 521,900 breast cancer deaths in 2008 (Torre et al, 2015). Cervical cancer is the second most diagnosed cancer and third leading cause of deaths in females, accounting for about 527600 new cases and 265700 deaths (Torre et al, 2015). Despite several advancements in recent years, contemporary anticancer therapy suffers from several limitations owing to their associated toxicity and off-target effects. This provokes an urgent need to design novel drugs with high efficacy specific for cancer cells and less toxicity to off-target cells. Phytochemicals have shown promise in this regard as they fit the above criteria, and their usage in anticancer therapy is an emerging trend
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