ML216-Induced BLM Helicase Inhibition Sensitizes PCa Cells to the DNA-Crosslinking Agent Cisplatin

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-12, Vol.27 (24), p.8790
• Main Authors: Ma, Xiao-Yan, Zhao, Jia-Fu, Ruan, Yong, Zhang, Wang-Ming, Zhang, Lun-Qing, Cai, Zheng-Dong, Xu, Hou-Qiang
• Format: Article
• Language: English
• Subjects: Analysis; Androgens; Antineoplastic Agents - pharmacology; Apoptosis; BLM inhibitor; Bloom's syndrome; Cancer; Cancer therapies; Caspase-3; CDDP; Cell cycle; Cell Line, Tumor; Cell lines; Cell viability; Chemotherapy; CHK1 protein; CHK2 protein; Cisplatin; Cisplatin - pharmacology; combined therapy; Comet assay; Crosslinked polymers; Crosslinking; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA - pharmacology; DNA Damage; DNA helicase; DNA repair; Drug therapy, Combination; Gene expression; Health aspects; Humans; Metastasis; ML216; Online databases; Prostate cancer; Radiation; RecQ Helicases - genetics; Synergistic effect; Toxicity; Tumors; Western blotting
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27248790

Using standard DNA-damaging medicines with DNA repair inhibitors is a promising anticancer tool to achieve better therapeutic responses and reduce therapy-related side effects. Cell viability assay, neutral comet assay, western blotting (WB), and cell cycle and apoptosis analysis were used to determine the synergistic effect and mechanism of ML216, a Bloom syndrome protein (BLM) helicase inhibitor, and cisplatin (CDDP), a DNA-crosslinking agent, in PCa cells. Based on the online database research, our findings revealed that BLM was substantially expressed in PCa, which is associated with a bad prognosis for PCa patients. The combination of ML216 and CDDP improved the antiproliferative properties of three PCa cell lines. As indicated by the increased production of γH2AX and caspase-3 cleavage, ML216 significantly reduced the DNA damage-induced high expression of BLM, making PC3 more susceptible to apoptosis and DNA damage caused by CDDP. Furthermore, the combination of ML216 and CDDP increased p-Chk1 and p-Chk2 expression. The DNA damage may have triggered the ATR-Chk1 and ATM-Chk2 pathways simultaneously. Our results demonstrated that ML216 and CDDP combination therapy exhibited synergistic effects, and combination chemotherapy could be a novel anticancer tactic.