A novel 3-acyl isoquinolin-1(2H)-one induces G2 phase arrest, apoptosis and GSDME-dependent pyroptosis in breast cancer

Breast cancer is the most common malignancy among women worldwide, accordingly, numerous chemotherapeutic drugs have been discovered thus far. However, the development and application of these drugs is severely constrained because of their unclear mechanism. To address this issue, our previous work has defined 3-acyl isoquinolin-1(2H)-one derivatives as potent anti-tumor agents, among which the compound 4f possessed relatively higher activity in vitro. In this study, we aim to further explore the anti-cancer effect and the underlying molecular mechanism of 4f in breast cancer cells. Therefore, CCK8 assay was used to detect cell viability and flow cytometry was used to analyze cell cycle and apoptosis. Meanwhile, related proteins that regulate cell cycle and apoptosis were detected. The results showed that 4f induced cell apoptosis and inhibited cell proliferation in breast cancer cells in a dose-depended manner without significant toxicity to human normal mammary epithelial cell. The cell cycle was arrested at G2 phase with the suppressed expression of the CDK1 protein. Additionally, 4f was confirmed to induce the cell apoptosis with the up-regulation of bax, down-regulation of bcl-2, activation of cleaved-caspase3/7/9 and cleaved-PARP, together with the inhibition of MEK/ERK and p38 MAPK pathway. Moreover, the GSDME-mediated pyroptosis was also induced by 4f in breast cancer cells. Together, these results demonstrated that 4f could serve as a new and promising candidate for the treatment of breast cancer.