Renner Kathrin, Seilbeck Anton, Kauer Nathalie, Ugele Ines, Siska Peter J, Brummer Christina, Bruss Christina, Decking Sonja-Maria, Fante Matthias, Schmidt Astrid, Hammon Kathrin, Singer Katrin, Klobuch Sebastian, Thomas Simone, Gottfried Eva, Peter Katrin, Kreutz Marina
Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany.
Front Pharmacol. 2018 Nov 2;9:1258. doi: 10.3389/fphar.2018.01258. eCollection 2018.
The accelerated metabolism of tumor cells, inevitable for maintaining high proliferation rates, is an emerging target for tumor therapy. Increased glucose and lipid metabolism as well as mitochondrial activity have been shown in solid tumors but also in leukemic cells. As tumor cells are able to escape the blockade of one metabolic pathway by a compensatory increase in other pathways, treatment strategies simultaneously targeting metabolism at different sites are currently developed. However, the number of clinically applicable anti-metabolic drugs is still limited. Here, we analyzed the impact of the anti-diabetic drug metformin alone or in combination with two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and diflunisal on acute myeloid leukemia (AML) cell lines and primary patient blasts. Diclofenac but not diflunisal reduced lactate secretion in different AML cell lines (THP-1, U937, and KG-1) and both drugs increased respiration at low concentrations. Despite these metabolic effects, both NSAIDs showed a limited effect on tumor cell proliferation and viability up to a concentration of 0.2 mM. In higher concentrations of 0.4-0.8 mM diflunisal alone exerted a clear effect on proliferation of AML cell lines and blocked respiration. Single treatment with the anti-diabetic drug metformin blocked mitochondrial respiration, but proliferation and viability were not affected. However, combining all three drugs exerted a strong cytostatic and cytotoxic effect on THP-1 cells. Comparable to the results obtained with THP-1 cells, the combination of all three drugs significantly reduced proliferation of primary leukemic blasts and induced apoptosis. Furthermore, NSAIDs supported the effect of low dose chemotherapy with cytarabine and reduced proliferation of primary AML blasts. Taken together we show that low concentrations of metformin and the two NSAIDs diclofenac and diflunisal exert a synergistic inhibitory effect on AML proliferation and induce apoptosis most likely by blocking tumor cell metabolism. Our results underline the feasibility of applying anti-metabolic drugs for AML therapy.
肿瘤细胞的加速代谢是维持高增殖率所必需的，正成为肿瘤治疗的一个新靶点。实体瘤以及白血病细胞中均已显示出葡萄糖和脂质代谢增加以及线粒体活性增强。由于肿瘤细胞能够通过其他途径的代偿性增加来逃避一种代谢途径的阻断，目前正在开发同时针对不同部位代谢的治疗策略。然而，临床上可应用的抗代谢药物数量仍然有限。在此，我们分析了抗糖尿病药物二甲双胍单独使用或与两种非甾体抗炎药双氯芬酸和二氟尼柳联合使用对急性髓系白血病（AML）细胞系和原发性患者原始细胞的影响。双氯芬酸而非二氟尼柳可降低不同AML细胞系（THP-1、U937和KG-1）中的乳酸分泌，且两种药物在低浓度时均可增加呼吸作用。尽管有这些代谢效应，但在浓度高达0.2 mM时，两种非甾体抗炎药对肿瘤细胞增殖和活力的影响有限。在0.4 - 0.8 mM的较高浓度下，单独使用二氟尼柳对AML细胞系的增殖有明显影响并阻断呼吸作用。抗糖尿病药物二甲双胍单药治疗可阻断线粒体呼吸，但不影响增殖和活力。然而，三种药物联合使用对THP-1细胞具有强大的细胞生长抑制和细胞毒性作用。与用THP-1细胞获得的结果相似，三种药物联合使用可显著降低原发性白血病原始细胞的增殖并诱导凋亡。此外，非甾体抗炎药可增强低剂量阿糖胞苷化疗的效果并降低原发性AML原始细胞的增殖。综上所述，我们表明低浓度的二甲双胍以及两种非甾体抗炎药双氯芬酸和二氟尼柳对AML增殖具有协同抑制作用，并最有可能通过阻断肿瘤细胞代谢诱导凋亡。我们的结果强调了应用抗代谢药物治疗AML的可行性。
