Effect of the IDH1 inhibitor combined with hypomethylating agents on acute myeloid leukemia.

IF 2 4区医学 Q3 ONCOLOGY

Tumori Pub Date : 2025-06-19 DOI:10.1177/03008916251346563

Yan Cheng, Hongwei Wu

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引用次数: 0

Abstract

Objective: Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in approximately 6-10% of acute myeloid leukemia (AML) patients. Ivosidenib (IVO) is a small-molecule inhibitor of mutant IDH1. This study delves into the mechanism of IVO with hypomethylating agents (HMAs) (azacitidine or decitabine) for treating IDH1-mutated AML through the PI3K/AKT pathway.

Methods: IDH1^R132H-mutated MOLM-13 (IDH1^R132H-MOLM-13) cells were constructed. The effects of the drugs, both individually and in combination, on IDH1^R132H-MOLM-13 cell proliferation and apoptosis were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and flow cytometry, with combination index (CI) values calculated using CompuSyn software. IDH1, DNMT1, PI3K and AKT gene mRNA levels, and the PI3K/AKT pathway- and histone lysine methylation-related protein levels in IDH1^R132H-MOLM-13 cells were determined by RT-qPCR and Western blot.

Results: IDH1^R132H-mutated MOLM-13 cells (IDH1^R132H-MOLM-13) were successfully constructed. The IDH1 inhibitor, either as a monotherapy or combined with HMAs, effectively inhibited IDH1^R132H-MOLM-13 cell proliferation, and the combination therapy exhibited synergistic effects (CI < 1). The combination therapy increased cell proportion in the G2/M phase and apoptotic rate. Both treatment modalities reduced IDH1, DNMT1, PI3K and AKT mRNA levels and histone lysine methylation levels (H3K4me3, H3K9me3, H3K27me3); besides, PI3K and AKT phosphorylation levels were reduced, with the reductions being more significant in cells undergoing combination therapy. The indexes did not differ significantly between cells undergoing the two modalities of combined treatments.

Conclusion: The IDH1 inhibitor with HMAs suppressed IDH1^R132H-MOLM-13 cell proliferation and viability and decreased the methylation level by repressing the phosphorylation of the PI3K/AKT pathway, showing a synergistic inhibitory effect.

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IDH1抑制剂联合低甲基化药物治疗急性髓系白血病的疗效。

目的：编码异柠檬酸脱氢酶1 （IDH1）的基因突变发生在大约6-10%的急性髓性白血病（AML）患者中。Ivosidenib （IVO）是一种突变型IDH1的小分子抑制剂。本研究探讨了低甲基化药物（HMAs）（阿扎胞苷或地西他滨）通过PI3K/AKT途径治疗idh1突变的AML的IVO机制。方法：构建idh1r132h突变的MOLM-13 （IDH1R132H-MOLM-13）细胞。采用3-（4,5 -二甲基噻唑-2-基）- 2,5 -二苯基溴化四唑和流式细胞术评估药物单独和联合对IDH1R132H-MOLM-13细胞增殖和凋亡的影响，使用CompuSyn软件计算联合指数（CI）值。采用RT-qPCR和Western blot检测IDH1R132H-MOLM-13细胞中IDH1、DNMT1、PI3K和AKT基因mRNA水平，以及PI3K/AKT通路和组蛋白赖氨酸甲基化相关蛋白水平。结果：成功构建了idh1r132h突变的MOLM-13细胞（IDH1R132H-MOLM-13）。IDH1抑制剂单药或联用HMAs均能有效抑制IDH1R132H-MOLM-13细胞增殖，且联用具有协同效应（CI < 1）。联合用药可提高G2/M期细胞比例和细胞凋亡率。两种治疗方式均降低了IDH1、DNMT1、PI3K和AKT mRNA水平和组蛋白赖氨酸甲基化水平（H3K4me3、H3K9me3、H3K27me3）；此外，PI3K和AKT磷酸化水平降低，且在联合治疗的细胞中降低更为明显。在接受两种联合治疗方式的细胞之间，这些指标没有显着差异。结论：含HMAs的IDH1抑制剂通过抑制PI3K/AKT通路磷酸化，抑制IDH1R132H-MOLM-13细胞增殖和活力，降低甲基化水平，具有协同抑制作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Tumori 医学-肿瘤学

CiteScore

3.50

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Tumori Journal covers all aspects of cancer science and clinical practice with a strong focus on prevention, translational medicine and clinically relevant reports. We invite the publication of randomized trials and reports on large, consecutive patient series that investigate the real impact of new techniques, drugs and devices inday-to-day clinical practice.