Switzeny Olivier, Pusch Stefan, Christmann Markus, Kaina Bernd
Institute of Toxicology, University Medical Center, 55131 Mainz, Germany.
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Biomedicines. 2025 Jun 16;13(6):1479. doi: 10.3390/biomedicines13061479.
: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are enzymes that catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), which is essential for many metabolic processes, including some steps in DNA repair. In tumors, notably in gliomas, and are frequently mutated. The mutation found in different cancers is functionally active, causing, instead of α-KG, the formation of 2-hydroxyglutarate (2-HG), which inhibits α-KG-dependent enzymes. Gliomas harboring mutated show a better prognosis than wild-type (wt) tumors of the same grade, which might result from the inhibition of DNA repair functions. A DNA repair enzyme dependent on α-KG is alkB homolog 2 (ALKBH2), which removes several lesions from DNA. These findings prompted us to investigate the response of glioma cells to artesunate (ART), a plant ingredient with genotoxic and anticancer activity currently used in several trials. : We used isogenic glioblastoma cell lines that express IDH1 wild-type or, based on a TET-inducible system, the IDH1 mutant (mt) protein, and treated them with increasing doses of artesunate. We also treated glioblastoma cells with 2-HG, generated ALKBH2 knockout cells, and checked their sensitivity to the cytotoxic effects of artesunate. : We show that the cell-killing effect of ART is enhanced if the IDH1 mutant (R132H) is expressed in glioblastoma cells. Further, we show that 2-HG imitates the effect of IDH1mt as 2-HG ameliorates the cytotoxicity of ART. Finally, we demonstrate that the knockout of ALKBH2 causes the sensitization of glioblastoma cells to ART. : The data indicate that ALKBH2 protects against the anticancer effect of ART, and the mutation of IDH1/2 commonly occurring in low-grade gliomas sensitizes to ART via an ALKBH2-dependent mechanism. The data support the use of ART in the therapy of -mutated cancers both in combination with chemotherapy and adjuvant treatment.
异柠檬酸脱氢酶1和2（IDH1和IDH2）是催化异柠檬酸氧化脱羧生成α-酮戊二酸（α-KG）的酶，α-KG对许多代谢过程至关重要，包括DNA修复的一些步骤。在肿瘤中，尤其是在胶质瘤中，IDH1和IDH2经常发生突变。在不同癌症中发现的这种突变具有功能活性，导致生成2-羟基戊二酸（2-HG）而非α-KG，2-HG会抑制α-KG依赖性酶。携带IDH1突变的胶质瘤比相同级别的野生型（wt）肿瘤预后更好，这可能是由于DNA修复功能受到抑制。一种依赖α-KG的DNA修复酶是alkB同源物2（ALKBH2），它能去除DNA上的多种损伤。这些发现促使我们研究胶质瘤细胞对青蒿琥酯（ART）的反应，青蒿琥酯是一种具有遗传毒性和抗癌活性的植物成分，目前正在多项试验中使用。我们使用了表达IDH1野生型或基于四环素诱导系统表达IDH1突变体（mt）蛋白的同基因胶质母细胞瘤细胞系，并用递增剂量的青蒿琥酯处理它们。我们还用2-HG处理胶质母细胞瘤细胞，生成ALKBH2基因敲除细胞，并检测它们对青蒿琥酯细胞毒性作用的敏感性。我们表明，如果在胶质母细胞瘤细胞中表达IDH1突变体（R132H），ART的细胞杀伤作用会增强。此外，我们表明2-HG模拟了IDH1mt的作用，因为2-HG改善了ART的细胞毒性。最后，我们证明敲除ALKBH2会使胶质母细胞瘤细胞对ART敏感。数据表明ALKBH2可抵御ART的抗癌作用，低级别胶质瘤中常见的IDH1/2突变通过依赖ALKBH2的机制使细胞对ART敏感。这些数据支持将ART用于治疗IDH突变的癌症，无论是与化疗联合还是辅助治疗。
