Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin.
Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin.
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用FDA批准的利托那韦和二甲双胍靶向多发性骨髓瘤的代谢可塑性。
DOI：
10.1158/1078-0432.ccr-14-1088
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发表时间：
2015-03-01
期刊：
影响因子：
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通讯作者：
Shanmugam M
中科院分区：
文献类型：
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作者：
Dalva-Aydemir S;Bajpai R;Martinez M;Adekola KU;Kandela I;Wei C;Singhal S;Koblinski JE;Raje NS;Rosen ST;Shanmugam M
我们之前已经证明，利托那韦靶向糖酵解对多发性骨髓瘤细胞的子集具有生长抑制性和细胞毒性。在本研究中，我们的目的是研究利托那韦耐药的代谢基础，并确定与线粒体复合物 I 抑制剂二甲双胍联合治疗以靶向代偿代谢的效用。我们确定了利托那韦和二甲双胍的组合指数、对骨髓瘤细胞系、患者样本和骨髓瘤异种移植物生长的影响。还对乳腺癌、黑色素瘤和卵巢癌细胞系进行了额外的评估。在多发性骨髓瘤细胞系和肿瘤裂解物中评估了与抑制促存活 BCL-2 家族成员 MCL-1 有关的信号传导。通过评估耗氧量来确定对氧化代谢的依赖，并通过估计特定代谢扰动背景下代谢物撤回后的活力来评估对谷氨酰胺的依赖。利托那韦治疗的多发性骨髓瘤细胞表现出对谷氨酰胺代谢的依赖性增加。利托那韦使多发性骨髓瘤细胞对二甲双胍敏感，在多发性骨髓瘤的体外和体内异种移植模型以及乳腺癌、卵巢癌和黑色素瘤癌细胞系中有效地引发细胞毒性。利托那韦和二甲双胍在体外和体内有效抑制多发性骨髓瘤细胞系中的 AKT 和 mTORC1 磷酸化以及促存活 BCL-2 家族成员 MCL-1 的表达。 FDA 批准的利托那韦和二甲双胍有效靶向多发性骨髓瘤细胞代谢，从而在多发性骨髓瘤中引发细胞毒性。我们的研究值得进一步研究重新利用利托那韦和二甲双胍来靶向骨髓瘤的代谢可塑性，更广泛地靶向骨髓瘤异质性并防止化疗耐药的侵袭性多发性骨髓瘤的再次出现。
We have previously demonstrated that ritonavir targeting of glycolysis is growth inhibitory and cytotoxic in a subset of multiple myeloma cells. In this study, our objective was to investigate the metabolic basis of resistance to ritonavir and to determine the utility of cotreatment with the mitochondrial complex I inhibitor metformin to target compensatory metabolism. We determined combination indices for ritonavir and metformin, impact on myeloma cell lines, patient samples, and myeloma xenograft growth. Additional evaluation in breast, melanoma, and ovarian cancer cell lines was also performed. Signaling connected to suppression of the prosurvival BCL-2 family member MCL-1 was evaluated in multiple myeloma cell lines and tumor lysates. Reliance on oxidative metabolism was determined by evaluation of oxygen consumption, and dependence on glutamine was assessed by estimation of viability upon metabolite withdrawal in the context of specific metabolic perturbations. Ritonavir-treated multiple myeloma cells exhibited increased reliance on glutamine metabolism. Ritonavir sensitized multiple myeloma cells to metformin, effectively eliciting cytotoxicity both in vitro and in an in vivo xenograft model of multiple myeloma and in breast, ovarian, and melanoma cancer cell lines. Ritonavir and metformin effectively suppressed AKT and mTORC1 phosphorylation and prosurvival BCL-2 family member MCL-1 expression in multiple myeloma cell lines in vitro and in vivo. FDA-approved ritonavir and metformin effectively target multiple myeloma cell metabolism to elicit cytotoxicity in multiple myeloma. Our studies warrant further investigation into repurposing ritonavir and metformin to target the metabolic plasticity of myeloma to more broadly target myeloma heterogeneity and prevent the reemergence of chemoresistant aggressive multiple myeloma.