Disulfiram potentiates cisplatin-induced apoptosis in small cell lung cancer via the inhibition of cystathionine β-synthase and H(2)S.

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 H(2)S level, and increased the level of ROS. The elevation of H(2)S 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.