Disulfiram potentiates cisplatin-induced apoptosis in small cell lung cancer via the inhibition of cystathionine β-synthase and H2S.

Abstract

Small cell lung cancer (SCLC) is a highly malignant neuroendocrine tumor. Platinum-based chemo-resistance is the major issue for the treatment of SCLC. The objective of the study is to identify the drugs that enhance anti-tumor activity of cisplatin (CDDP) in SCLC. Firstly, by a high-throughput drug screening, we found that disulfiram (DSF), a FDA-approved drug that is used to treat alcohol addiction, was able to sensitize CDDP-induced apoptosis in SCLC. RNA-seq analysis revealed that cystathionine β-synthase (CBS) was a potential target of combination treatment of DSF and CDDP in SCLC. CDDP treatment induced CBS expression, while the elevation of CBS expression was down-regulated by DSF and CDDP co-treatment in SCLC. Importantly, the down-regulation of CBS by siRNA silence increased CDDP-induced cellular apoptosis in SCLC. Furthermore, the study found that DSF combined with CDDP decreased the H₂S level, and increased the level of ROS. The elevation of H₂S level reduced the growth inhibition of SCLC cells by DSF and CDDP co-treatment. Finally, in nude mice bearing SCLC xenografts, DSF and CDDP co-treatment exhibited remarkable anti-tumor activity against SCLC tumors, evidenced by the significant reduction of tumor size, tumor weight and Ki-67 expression as compared with single treatment alone. Therefore, the study indicated that DSF could be re-purposed to potentiate CDDP-induced anti-tumor activity in SCLC, which are worth immediate assessment for SCLC in clinical settings.