Metformin and FTY720 Synergistically Induce Apoptosis in Multiple Myeloma Cells
Metformin and FTY720 Synergistically Induce Apoptosis in Multiple Myeloma Cells
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二甲双胍和 FTY720 协同诱导多发性骨髓瘤细胞凋亡。
DOI：
10.1159/000491908
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发表时间：
2018-07
影响因子：
--
通讯作者：
Rui Yu
中科院分区：
文献类型：
--
作者：
Yi Zhao;Enfan Zhang;Ning Lv;Liang Ma;Shunnan Yao;Meidi Yan;Fumin Zi;Gang Deng;Xinling Liu;Jingsong He;Wenjun Wu;Zhen Cai;Rui Yu
背景/目的：多发性骨髓瘤（MM）患者总是复发为化疗耐药疾病，强调需要新的治疗方案绕过这些耐药机制。二甲双胍是一种广泛使用的抗糖尿病药物，对多种肿瘤细胞系具有直接的抗肿瘤活性。FTY720，也被称为fingolimod，是一种免疫调节剂，已被FDA批准作为口服药物治疗复发型多发性硬化症（MS）。近年来，FTY720因其抗肿瘤活性而备受关注。为了探索一种优化的联合治疗方法，我们在MM细胞中检测了二甲双胍和FTY720之间的相互作用。方法：采用MTT法测定MM细胞活力。凋亡核小体测定法检测细胞凋亡。流式细胞术检测线粒体膜电位损失（MMP， ΔΨm）和细胞ROS水平。采用qRT-PCR分析mrna的表达。Western blotting检测不同信号通路中蛋白的表达水平。结果：二甲双胍与FTY720共给药可协同抑制MM细胞的增殖。二甲双胍和FTY720共处理后，检测到细胞凋亡水平升高、caspase-3活化和PARP裂解。这些事件与Bcl-2蛋白的调节、MMP的缺失、内质网应激诱导和PI3K/AKT/mTOR信号通路的抑制有关。二甲双胍/FTY720方案显著诱导ROS生成；此外，活性氧清除剂NAC可减轻细胞凋亡、内质网应激和对PI3K/AKT/ mTOR的抑制。结论：二甲双胍联合FTY720暴露能以ros依赖的方式诱导MM细胞凋亡，表明联合这些药物的策略值得在MM中进一步研究。
Background/Aims: Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new therapeutic options that bypass these resistance mechanisms. Metformin is a widely prescribed antidiabetic drug with direct antitumor activity against various tumor cell lines. FTY720, also known as fingolimod, is an immune-modulating agent approved by the FDA as oral medication to treat the relapsing form of multiple sclerosis (MS). In recent years, FTY720 has attracted attention due to its anti-tumor activity. To explore an optimized combinational therapy, interactions between metformin and FTY720 were examined in MM cells. Methods: MTT assays were employed to assess the viability of MM cells. An apoptotic nucleosome assay was employed to measure apoptosis. Loss of mitochondrial membrane potential (MMP, ΔΨm) and cellular levels of ROS were measured by flow cytometry. qRT-PCR was used to analyze the expression of mRNAs. Western blotting assays were applied to measure the levels of proteins involved in different signaling pathways. Results: Coadministration of metformin and FTY720 synergistically inhibited the proliferation of MM cells. Increased levels of apoptosis, activation of caspase-3 and cleavage of PARP were detected after cotreatment with metformin and FTY720. These events were associated with modulation of Bcl-2 proteins, loss of MMP, ER stress induction, and inhibition of the PI3K/AKT/mTOR signaling pathway. The metformin/FTY720 regimen markedly induced ROS generation; moreover, apoptosis, ER stress and inhibition of PI3K/AKT/ mTOR were attenuated by the ROS scavenger NAC. Conclusions: Exposure to metformin in combination with FTY720 potently induces apoptosis in MM cells in a ROS-dependent manner, suggesting that a strategy combining these agents warrants further investigation in MM.
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DOI：
10.2217/14796694.3.6.639
发表时间：
2007-12-01
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Harvey, R Donald;Lonial, Sagar
通讯作者：
Lonial, Sagar
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
发表时间：
2015-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
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
通讯作者：
Shanmugam M
影响因子：
4.6
作者：
Mogavero A;Maiorana MV;Zanutto S;Varinelli L;Bozzi F;Belfiore A;Volpi CC;Gloghini A;Pierotti MA;Gariboldi M
通讯作者：
Gariboldi M
影响因子：
4.8
作者：
Ling, YH;Liebes, L;Perez-Soler, R
通讯作者：
Perez-Soler, R
影响因子：
3.1
作者：
Chou, Yi-Sheng;Yang, Ching-Fen;Hsiao, Liang-Tsai
通讯作者：
Hsiao, Liang-Tsai