Abstract
Phospholipases A2(PLA2s) overexpression is closely associated with the malignant potential of breast cancers. Here, we showed for the first the antitumoral effects of γCdcPLI, a PLA2 inhibitor from Crotalus durissus collilineatus via PI3K/Akt pathway on MDA-MB-231 cell. Firstly, γCdcPLI was more cytotoxic to MDA-MB-231 breast cancer cells than other cell lines (MCF-7, HeLa, PC3 and A549) and did not affect the viability of non-tumorigenic breast cell (MCF 10A). In addition, γCdcPLI induced modulation of important mediators of apoptosis pathways such as p53, MAPK-ERK, BIRC5 and MDM2. γCdcPLI decreased MDA-MB-231 adhesion, migration and invasion. Interestingly, the γCdcPLI also inhibited the adhesion and migration of endothelial cells and blocked angiogenesis by inhibiting tube formation by HUVECs in vitro and sprouting elongation on aortic ring assay ex vivo. Furthermore, γCdcPLI reduced the production of vascular endothelial growth factor (VEGF). γCdcPLI was also able to decrease PGE2 levels in MDA-MB-231 and inhibited gene and protein expression of the PI3K/Akt pathway. In conclusion, γCdcPLI showed in vitro antitumoral, antimestatatic and anti-angiogenic potential effects and could be an attractive approach for futures studies in cancer therapy.
Highlights
Breast cancer is the second most common cancer in women while new cases worldwide are increasing every year
PLA2s participate in anti-apoptotic pathways and can be found overexpressed in different types of breast cancer cells; their overexpression is closely associated with the malignant potential of breast cancers[6, 15,16,17,18]
In the same concentration of IC50 value of MDA-MB-231, γCdcPLI did not significantly affect the viability of non-tumorigenic MCF 10A cells (***p < 0.001). These results suggest that γCdcPLI is more cytotoxic to breast cancer cells (MDA-MB-231 and MCF-7) than others cancer cell lines and to non-tumorigenic breast cells
Summary
Breast cancer is the second most common cancer in women while new cases worldwide are increasing every year. During the past ten years several studies have shown the molecular aspects of breast cancer as being related to loss of cellular contact inhibition, insensitivity to antigrowth signals and resistance to apoptosis[1, 3,4,5] Many of these mechanisms involved in breast cancer cell survival are associated with the expression and activity of secretory phospholipases A2 (sPLA2) and membrane-associated PLA2 (M-PLA2)[5,6,7,8,9,10,11,12]. Donnini et al.[20] showed cytotoxic and antiproliferative effects on different cancer cells lines, as well as reduction of tumor growth in nude mice transplanted with A431 tumor cells treated with a PLA2 inhibitor from Pyton sebae snake serum These works open up new pathways to exploring the therapeutic potential of PLA2 inhibitors from snake serum
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