Wang Haiqin, Zhang Yibin, Jiang Yu, Xiang Ruohong, Gong Han, Gong Yanfei, Xu Hao, Ma Zekang, Xie Yifang, Zhu Yu, Hu Bin, He Xiao, Liu Jing, Zhang Ji, Xiao Xiaojuan
Department of Hematology, the Second Xiangya Hospital, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410011, Hunan, China.
Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China.
Biochem Pharmacol. 2025 Feb;232:116717. doi: 10.1016/j.bcp.2024.116717. Epub 2024 Dec 14.
Multiple myeloma (MM) is an incurable malignant hematological neoplasm characterized by clonal proliferation of plasma cells accumulating in the bone marrow. Currently, the treatment of MM is usually based on a multi-drug combination strategy, and the remission rates of MM patients have been greatly improved. However, MM is still not immune to drug resistance and recurrence and is an incurable tumor. In this study, a comprehensive screen of the TCA cycle identified oxoglutarate dehydrogenase (OGDH) and pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) as the most clinically relevant genes in MM, highlighting their potential as therapeutic targets. CPI-613, a novel non-redox-active lipoic acid analog that causes mitochondrial metabolism dysfunction by targeting OGDH and PDHA1, is currently in clinical trials in a variety of malignancies. In our study, CPI-613 was found to inhibit the proliferation of MM cells, and its combination with bortezomib (BTZ) produced a significant inhibitory effect at lower doses. In addition, CPI-613 can disrupt various mitochondrial functions, such as disrupting mitochondrial morphology, reducing oxidative phosphorylation, decreasing 5'- adenylate triphosphate production, and increasing reactive oxygen species, which ultimately leads to cell death mediated by the intrinsic apoptotic pathway in vitro. Furthermore, we found CPI-613 significantly inhibited tumor growth and induced intrinsic apoptosis in the MM mouse xenograft model. This study reveals the mechanism and effect of CPI-613 in MM, which suggests that CPI-613 may be a new drug option for the clinical treatment of MM, but further clinical trials are needed for evaluation.
多发性骨髓瘤（MM）是一种无法治愈的恶性血液肿瘤，其特征是骨髓中浆细胞的克隆性增殖。目前，MM的治疗通常基于多药联合策略，MM患者的缓解率已得到显著提高。然而，MM仍然无法避免耐药性和复发，是一种无法治愈的肿瘤。在本研究中，通过对三羧酸循环（TCA循环）的全面筛查，确定了氧代戊二酸脱氢酶（OGDH）和丙酮酸脱氢酶E1亚基α1（PDHA1）是MM中最具临床相关性的基因，突出了它们作为治疗靶点的潜力。CPI-613是一种新型的非氧化还原活性硫辛酸类似物，通过靶向OGDH和PDHA1导致线粒体代谢功能障碍，目前正在多种恶性肿瘤中进行临床试验。在我们的研究中，发现CPI-613可抑制MM细胞的增殖，并且它与硼替佐米（BTZ）联合使用在较低剂量时产生了显著的抑制作用。此外，CPI-613可破坏各种线粒体功能，如破坏线粒体形态、降低氧化磷酸化、减少三磷酸腺苷（ATP）生成以及增加活性氧，这最终导致体外通过内源性凋亡途径介导的细胞死亡。此外，我们发现CPI-613在MM小鼠异种移植模型中显著抑制肿瘤生长并诱导内源性凋亡。本研究揭示了CPI-613在MM中的作用机制和效果，这表明CPI-613可能是MM临床治疗的一种新药选择，但需要进一步的临床试验进行评估。
