Novel Sulforaphane Analog Disrupts Phosphatidylinositol-3-Kinase-Protein Kinase B Pathway and Inhibits Cancer Cell Progression via Reactive Oxygen Species-Mediated Caspase-Independent Apoptosis
Ananya Dutta, Satyajit Halder, Ishani Bhaumik, Utsab Debnath, Debashis Dhara, Anup Kumar Misra, Kuladip Jana
Abstract
Sulforaphane, a naturally occurring isothiocyanate, has gained attention due to its tremendous anticancer potential. Thus, an array of sulforaphane analogs were synthesized and evaluated for their cytotoxic potentials on a wide range of malignant cell lines. Among these derivatives, compound 4a displayed exceptional potency in inhibiting the proliferation of cancer cell lines and a negligible effect on normal cell lines through G2/M phase arrest. The lead compound induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction, leading to apoptosis. Further mechanistic studies established the interaction of the compound 4a with the insulin-like growth factor-1 receptor (IGF-R1) and blocking of the phosphatidylinositol-3-kinase ( PI3K )-protein kinase B (PKB/Akt) pathway. This led to suppression of nuclear factor erythroid 2-related factor 2 (NRF-2) protein expression, thus increasing the free radicals in the tumor cells. Moreover, compound 4a induced ROS-mediated caspase-independent apoptosis. Finally, compound 4a reduced tumor progression in a 4T1 injected BALB/c syngeneic mice tumor model. In conclusion, this study summarizes the mechanism of compound 4a -mediated ROS-mediated caspase-independent apoptosis. According to the study’s findings, compound 4a can be used as a powerful new anticancer agent to enhance cancer treatment.