Identification of Novel Natural Compounds with Anti-Breast Cancer Activities
Breast cancer continues to be the leading cause of cancer-related death in women worldwide. In this dissertation, natural compounds with anti-breast cancer activities were identified. We investigated the effect of Salinomycin, a potassium ionophore isolated from Streptomyces albus, on the survival of three human breast cancer cell lines MCF-7, T47D and MDA-MB-231. High concentrations of Salinomycin induced a G2 arrest, down regulation of surviving and triggered apoptosis. Interestingly, treatments with low concentration of Salinomycin induced a transient G1 arrest at an earlier time and G2 arrest and senescence, associated with enlarged cell morphology, at a later time. There was also an upregulation of p21 protein, an increase in Histone H3 and H4 hyperacetylation and expression of SA- β-Gal activity. Furthermore, it was found that Salinomycin was able to potentiate the killing of the MCF-7 and MDA-MB-231 cells, by the chemotherapeutic agents, 4-Hydroxytamoxifen and frondoside A, we also investigated the effect of Origanum majorana, a culinary herb, ethanolic extract (OME) on the survival, migration, invasion and tumor growth of the highly proliferative and invasive triple-negative p53 mutant breast cancer cell line MDA-MB-231. We found that OME inhibited the viability of MDA-MB-231 breast cancer cells both in vitro and in vivo. OME was found to elicit anti-breast cancer activity by inducing mitotic arrest, DNA damage and triggering the extrinsic apoptotic pathway.
Moreover, OME was found to induce down regulation of survivin, an important therapeutic target against breast cancer. OME was also found to inhibit cell migration and invasion, two major events required for tumor metastasis. Our data are the first to link senescence and histone modifications to Salinomycin which provides a new insight to better understand the mechanism of action of Salinomycin, at least in breast cancer cells. Moreover, our findings provide strong evidence that O. majorana may be a promising chemopreventive and therapeutic candidate against cancer especially for highly invasive triple negative p53 mutant breast cancer; thus validating its use in alternative medicine.