Telomerase inhibition by MST-312 sensitises breast cancer cells to anti-cancer properties of Plumbagin

Abstract

Breast cancer is the most common cause of malignancy and the second most common cause of cancer death in women. This heterogeneous disease is currently broadly classified as ER, PG positive luminal tumours, HER2 amplified tumours and triple- negative breast cancers (TNBC). Natural plant derived compounds are proven to be promising anti-cancer chemotherapeutics agents with minimal cytotoxic effects on healthy cells. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) is a phytochemical derived from the roots of Plumbago zeylanica and it is known to possess anti-cancer properties similar to other compounds of naphthoquinones. In about 90 % of cancer cells, the telomerase enzyme activity is revived to add telomeric repeats to evade apoptosis. In this study, a combinatorial approach of combining anti-cancer compound Plumgagin to induce genotoxicity and a potent telomerase inhibitor, MST-312 (synthetic derivative of tea-catechins)was used to determine the synthetic lethality in breast cancer cells such as MDA-MB-231 (TNBC) and MCF-7 (lumina) cells. MDA-MB-231 cells were responsive to combination treatment to both short-term (48 hours) and long-term treatment (14 days) in a synergistic manner, whereas in MCF-7, the combination treatment was more effective in the long-term regimen. Furthermore, the cytotoxic effects of the Plumbagin and MST-312 combination treatment were not recoverable after the short-term treatment. In conclusion, combination treatment of MST-312 and Plumbagin is proven to be more effective than single Plumbagin compound treatment, in inducing DNA damage and telomere dysfunction leading to greater genome instability, cell cycle arrest and eventually cell death in cancer cells.