The factors responsible for the induction of cell death by
dimethoxycurcumin (Dimc), a synthetic analog of
curcumin, were assessed in human
breast carcinoma MCF7 cells. Initial cytotoxic studies with both
curcumin and Dimc using MTT assay indicated their comparable effects. Further, the mechanism of action was explored in terms of oxidative stress,
mitochondrial dysfunction, and modulation in the expression of
proteins involved in cell cycle regulation and apoptosis. Dimc (5-50 μM) caused generation of
reactive oxygen species, reduction in
glutathione level, and induction of DNA damage. The
mitochondrial dysfunction induced by Dimc was evidenced by the reduction in mitochondrial membrane potential and decrease in cellular energy status (
ATP/
ADP) monitored by HPLC analysis. The observed decrease in
ATP was also supported by the significant suppression of different (α, β, γ, and ε) subunits of
ATP synthase. The cytotoxic effect of Dimc was further characterized in terms of induction of S-phase cell cycle arrest and apoptosis, and their relative contribution was found to vary with the treatment concentration of Dimc. The S-phase arrest and apoptosis could also be correlated with the changes in the expressions of
cell cycle proteins like p53, p21, CDK4, and cyclin-D1 and apoptotic markers like Bax and Bcl-2. Overall, the results demonstrated that Dimc induced cell death in MCF7 cells through S-phase arrest and apoptosis.