Mechanism of the malabaricone C-induced toxicity to the MCF-7 cell line

In this study, we studied the mechanism of the cytotoxicity of malabaricone C (mal C) against human breast Cancer MCF-7 cell line. Mal C dose-dependently increased the sub G1 cell population, associated with cytoplasmic oligonucleosome formation and chromatin condensation. The mal C-induced Apoptosis led to mitochondrial damage as revealed by fluorescence microscopy and flow cytometry of the JC-1-stained cells as well as from the release of mitochondrion-specific nuclease proteins AIF and endo G. Mal C also released intracellular CA(2+) from the MCF-7 cells, but the CA(2+)-modulators BAPTA-AM and Ru360 only partially abrogated the Apoptosis. The calpain activation by mal C did not have any effect on its cytotoxicity. On the Other hand, after mal C treatment significant lysosomal membrane permeabilization (LMP), along with release of Cathepsin B, as well as Bid-cleavage and its translocation to mitochondria were observed much earlier than the mitochondrial damage. This suggested that cytotoxicity of mal C against human MCF-7 human breast Cancer cell line may proceed through LMP as the initial event that triggered a caspase-independent, but Cathepsin B and t-Bid-dependent intrinsic mitochondrial apoptotic pathway. A significant accumulation of cells in the S or G2-M phases along with upregulation of the cyclins E and A due to mal C exposure promises it to be a potential anti-cancer agent.