Autophagy inhibitor sensitizes MCF-7 breast cancer cells to novel cyclic tetrapeptide CTS203-induced caspase-9-dependent apoptotic cell death

Histone deacetylase (HDAC) inhibitors have been demonstrated to be effective anti-cancer candidates against aggressive malignancies. In previous study, a novel hydroxamic acid derivate, CTS203 cyclo(-L-Asu(NHOH)-L-A3mc6c-L-Phe-D-Pro-), demonstrated promising HDAC inhibitory activity. Herein, more biological evaluations including cell viability, cell cycle distribution, cellular morphology, expression quantification as well as protein-protein interactions were measured to investigate its cytotoxic mechanism. Corresponding with its significant HDAC inhibitory activity, CTS203 led to increased acetylation of H3K14, cell cycle arrest as well as consequent apoptotic cell death, with bearable influence on the viability of normal cells. However, schedule-dependent cytotoxicity against MCF-7 breast cancer cells revealed a delayed cellular response to chemo-stimuli. Within this corresponding period, autophagy was rapidly triggered once exposure started, whereas autophagy inhibitor sensitized MCF-7 cells to CTS203, exhibiting synergistically anti-proliferative effects. The expression variation in MCF-7 cells revealed that the cleavage of Beclin 1 mediated by caspase-8 resulted in disabled autophagy, thus ultimately facilitated and fastened caspase-9-dependent apoptotic cell death. Taken together, these findings elucidated the mechanism of CTS203-induced cytotoxicity as well as suggested that appropriate manipulation of autophagy would be an adjunctive strategy to enhance HDAC inhibitor-induced cell death.