SNS‑032 combined with decitabine induces caspase‑3/gasdermin E‑dependent pyroptosis in breast cancer cells

SNS-032 is a synthetic compound that specifically inhibits cyclin-dependent kinases 2, 7 and 9. Its primary Anticancer activity involves cell cycle arrest, which prevents tumor cell growth. However, there are limited reports on whether SNS-032 induces Pyroptosis, a novel inflammation-mediated programmed cell death pathway in breast Cancer (BC). The present study demonstrated that SNS-032 treatment decreased cell viability by inducing Pyroptosis in BC cells. Typical morphological indications of Pyroptosis were observed, including cell swelling and destruction of cell membrane integrity, leading the release of adenosine 5'-triphosphate and Lactate Dehydrogenase. Furthermore, the expression of Caspase-3, the N terminus of gasdermin E (GSDME) and B-cell lymphoma-2 (Bcl-2)-associated X protein increased, whereas expression of Bcl-2 decreased. In addition, Z-DEVD-FMK, a specific Caspase-3 inhibitor, markedly alleviated Pyroptosis triggered by SNS-032. These findings suggested that SNS-032 induced Caspase-3/GSDME-dependent Pyroptosis. Furthermore, the present study demonstrated that decitabine (DAC), a DNA Methyltransferase Inhibitor, upregulated the expression of GSDME protein and enhanced SNS-032-induced Caspase-3/GSDME-dependent Pyroptosis in BC cells. In conclusion, these results suggest that Caspase-3/GSDME-induced Pyroptosis can be facilitated by SNS-032 treatment in BC cells, and DAC has the potential to enhance SNS-032-induced Pyroptosis by increasing GSDME expression. This mechanistic insight indicates that SNS-032 is a promising therapeutic agent for BC treatment.

BC; SNS-032; caspase-3/GSDME; decitabine; pyroptosis.