The potent cytotoxicity of reactive oxygen species (ROS) can cause various diseases, however, it may also serve as a powerful chemotherapeutic strategy capable of killing cancer cells. Oxalomalate (OMA, α-hydroxy-β-oxalosuccinic acid), a tricarboxylic acid intermediate, is a well-known competitive inhibitor of two classes of NADP⁺-dependent isocitrate dehydrogenase (IDH) isoenzymes, which serve as the major antioxidants and redox regulators in the mitochondria and cytosol. In this study, we investigated the therapeutic effects of OMA in melanoma and elucidated the associated underlying mechanisms of action using in vitro and in vivo models. OMA targeting IDH enzymes suppressed melanoma growth through activation of apoptosis and inhibition of angiogenesis. Mechanistically, our findings showed that OMA activated p53-mediated apoptosis through ROS-dependent ATM-Chk2 signaling and reduced the expression of vascular endothelial growth factor through ROS-dependent E2F1-mediated hypoxia inducible factor-1α degradation. In particular, OMA-induced suppression of IDH activity resulted in induction of ROS stress response, ultimately leading to apoptotic cell death and antiangiogenic effects in melanoma cells. Thus, OMA might be a potential candidate drug for melanoma skin cancer therapy.

活性氧（ROS）的强细胞毒性可引起多种疾病，但是，它也可以作为一种强大的化学疗法来杀死癌细胞。草酸马草酸酯（OMA，α-羟基-β-草酰琥珀酸），一种三羧酸中间体，是两类NADP ⁺依赖性异柠檬酸脱氢酶（IDH）同工酶的著名竞争抑制剂，它们是主要的抗氧化剂和氧化还原调节剂在线粒体和细胞质中。在这项研究中，我们研究了黑素瘤OMA的治疗效果和阐明的动作相关联的底层机制使用体外和体内楷模。靶向IDH酶的OMA通过激活细胞凋亡和抑制血管生成来抑制黑色素瘤的生长。从机理上讲，我们的研究结果表明，OMA通过ROS依赖的ATM-Chk2信号激活了p53介导的细胞凋亡，并通过ROS依赖的E2F1介导的缺氧诱导因子1α降解而降低了血管内皮生长因子的表达。特别是，OMA诱导的IDH活性抑制导致ROS应激反应的诱导，最终导致黑素瘤细胞凋亡和死亡。因此，OMA可能是黑色素瘤皮肤癌治疗的潜在候选药物。