Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for therapeutic interventions. As a primary regulator of cellular homeostasis, carbonic anhydrases (CAs; EC 4.2.1.1) have emerged as promising molecular targets for the development of anticancer drugs. Within the present study, we tested the commercial drug acetazolamide and our previously discovered inhibitors to target the CAII isoform, which was overexpressed and positively correlated with ES patient relapse. We employed molecular biology tests to identify effective inhibitors of CAII that can induce ferroptosis by downregulating FTH1 expression in ES cells. In vitro, we have also demonstrated their ability to reduce cell proliferation, decrease invasion, and induce apoptosis- or autophagy-related cell death. Using Western blotting, we confirmed the induction of cathepsin B in cells treated with CA inhibitors. It was found that the suppression of cathepsin B expression during the treatment reduces the anticancer efficacy of selected CAII inhibitors. These experiments highlighted profound antitumor activity of CAII inhibitors attributive to their remarkable ability to trigger ferroptosis in Ewing sarcoma cells without causing substantial host damage. The obtained results suggest that cytosolic CAII may be a prospective target for ES treatment, and CAII inhibitors can be considered as potential single-agent or combination antitumor agents to be used in the treatment of ES.
尤文肉瘤是儿童最常见的恶性肿瘤类型之一。其细胞活跃的代谢状态为治疗干预提供了新的潜在靶点。碳酸酐酶作为细胞稳态的主要调节因子，已成为抗癌药物开发中极具前景的分子靶标。本研究针对在尤文肉瘤中过表达且与患者复发呈正相关的CAII亚型，测试了市售药物乙酰唑胺及我们先前发现的抑制剂。通过分子生物学实验，我们鉴定出能通过下调FTH1表达诱导尤文肉瘤细胞铁死亡的有效CAII抑制剂。体外实验进一步证明，这些抑制剂能够抑制细胞增殖、降低侵袭能力，并诱导细胞发生凋亡或自噬相关死亡。Western blotting实验证实CA抑制剂可诱导组织蛋白酶B的表达，而治疗过程中抑制该蛋白表达会降低所选CAII抑制剂的抗癌效果。这些实验凸显了CAII抑制剂通过显著触发尤文肉瘤细胞铁死亡而不造成明显宿主损伤的强大抗肿瘤活性。研究结果表明，胞质CAII可能成为尤文肉瘤治疗的潜在靶点，CAII抑制剂有望作为单药或联合用药方案应用于尤文肉瘤的临床治疗。
肿瘤(癌症)患者之家