DCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma. However, the underlying mechanism of its action remains unknown. We generated bortezomib (BTZ)-resistant cell lines, treated them with various concentrations of DCZ3301 over varying periods, and studied its effect on colony formation, cell proliferation, apoptosis, cell cycle, DNA synthesis, and DNA damage response. We validated our results using in vitro and in vivo experimental models. DCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G2/M checkpoint in multiple myeloma (MM) in vitro and in vivo. Furthermore, treatment of BTZ-resistant cells with DCZ3301 restored their drug sensitivity. DCZ3301 induced M phase cell cycle arrest in MM mainly via inhibiting DNA repair and enhancing DNA damage. Moreover, DCZ3301 promoted the phosphorylation of ATM, ATR, and their downstream proteins, and these responses were blocked by the ATM specific inhibitor KU55933. Our study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.

中文翻译：

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新型M相阻滞剂DCZ3301通过DNA损伤和有丝分裂灾难增强了硼替佐米在耐药性多发性骨髓瘤中的敏感性。

DCZ3301是我们小组先前报道的新型芳基胍基化合物，对多发性骨髓瘤（MM），弥漫性大B细胞淋巴瘤（DLBCL）和T细胞白血病/淋巴瘤具有细胞毒性作用。但是，其作用的潜在机制仍然未知。我们生成了抗硼替佐米（BTZ）的细胞系，并在不同时期内用不同浓度的DCZ3301处理它们，并研究了其对菌落形成，细胞增殖，凋亡，细胞周期，DNA合成和DNA损伤反应的影响。我们使用体外和体内实验模型验证了我们的结果。DCZ3301通过在体内外对多发性骨髓瘤（MM）中的G2 / M检查点进行调节，从而克服了硼替佐米（BTZ）耐药性。此外，用DCZ3301处理抗BTZ的细胞恢复了其药物敏感性。DCZ3301主要通过抑制DNA修复和增强DNA损伤来诱导MM中的M期细胞周期停滞。此外，DCZ3301促进了ATM，ATR及其下游蛋白的磷酸化，这些反应被ATM特异性抑制剂KU55933阻断。我们的研究提供了概念验证，可以保证对DCZ3301作为针对MM中BTZ耐药性的新型抗肿瘤化合物进行临床评估。