The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration.
The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration.
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DOI：
10.1016/j.molmet.2016.08.014
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发表时间：
2016-10
影响因子：
8.1
通讯作者：
Steinberg GR
中科院分区：
文献类型：
--
作者：
Villani LA;Smith BK;Marcinko K;Ford RJ;Broadfield LA;Green AE;Houde VP;Muti P;Tsakiridis T;Steinberg GR
钠-葡萄糖转运蛋白2（SGLT 2）抑制剂Canagliflozin和Dapagliflozin是最近批准的2型糖尿病药物。最近的研究表明，SGLT 2抑制剂可能抑制某些癌细胞的生长，但其机制尚不清楚。使用细胞增殖和克隆形成存活率评估前列腺癌和肺癌细胞生长对SGLT 2抑制剂的敏感性。评估耗氧量、细胞外酸化率、细胞ATP、葡萄糖摄取、脂肪生成和AMP活化蛋白激酶（AMPK）、乙酰辅酶A羧化酶和p70 S6激酶的磷酸化。使用维持复合物I支持的线粒体呼吸（NDI 1）的蛋白质的过表达来确定该途径对介导卡格列净抗增殖作用的重要性。临床可达到浓度的卡格列净（但不是达格列净）单独以及与电离辐射和化疗多西他赛联合使用时，可抑制前列腺癌和肺癌细胞的细胞增殖和克隆形成存活。卡格列净减少葡萄糖摄取、线粒体复合物-I支持的呼吸、ATP和脂肪生成，同时增加AMPK的活化磷酸化。NDI 1的过表达阻断了卡格列净的抗增殖作用，表明线粒体呼吸的减少对于抗增殖作用至关重要。这些数据表明，与双胍二甲双胍一样，卡格列净不仅降低血糖，而且抑制前列腺和肺癌细胞中复合物I支持的呼吸和细胞增殖。这些观察结果支持在临床前动物模型中开展评价卡格列净限制肿瘤发生的临床疗效的研究，以及在临床人群中开展相对于其他降糖治疗的癌症发生率的流行病学研究。卡格列净抑制癌细胞的增殖和克隆形成存活。卡格列净可增强放射和多西他赛的抗克隆形成作用。卡格列净减少葡萄糖摄取和复合物-I支持的呼吸。卡格列净降低细胞内ATP并抑制脂肪生成。代谢复合物-1支持呼吸逆转了卡格列净的作用。
The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 inhibitors may inhibit the growth of some cancer cells but the mechanism(s) remain unclear. Cellular proliferation and clonogenic survival were used to assess the sensitivity of prostate and lung cancer cell growth to the SGLT2 inhibitors. Oxygen consumption, extracellular acidification rate, cellular ATP, glucose uptake, lipogenesis, and phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase, and the p70S6 kinase were assessed. Overexpression of a protein that maintains complex-I supported mitochondrial respiration (NDI1) was used to establish the importance of this pathway for mediating the anti-proliferative effects of Canagliflozin. Clinically achievable concentrations of Canagliflozin, but not Dapagliflozin, inhibit cellular proliferation and clonogenic survival of prostate and lung cancer cells alone and in combination with ionizing radiation and the chemotherapy Docetaxel. Canagliflozin reduced glucose uptake, mitochondrial complex-I supported respiration, ATP, and lipogenesis while increasing the activating phosphorylation of AMPK. The overexpression of NDI1 blocked the anti-proliferative effects of Canagliflozin indicating reductions in mitochondrial respiration are critical for anti-proliferative actions. These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations. Canagliflozin inhibits the proliferation and clonogenic survival of cancer cells. Canagliflozin enhances the anti-clonogenic effects of radiation and Docetaxel. Canagliflozin reduces glucose uptake and complex-I supported respiration. Canagliflozin decreases intracellular ATP and inhibits lipogenesis. Bypassing complex-1 supported respiration reversed the effects of Canagliflozin.
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癌细胞对葡萄糖限制和双胍类药物敏感性的代谢决定因素。
影响因子：
64.8
作者：
Birsoy, Kivanc;Possemato, Richard;Lorbeer, Franziska K.;Bayraktar, Erol C.;Thiru, Prathapan;Yucel, Burcu;Wang, Tim;Chen, Walter W.;Clish, Clary B.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
78.5
作者：
Shackelford, David B.;Shaw, Reuben J.
通讯作者：
Shaw, Reuben J.
影响因子：
3.7
作者：
Aguer C;Gambarotta D;Mailloux RJ;Moffat C;Dent R;McPherson R;Harper ME
通讯作者：
Harper ME
影响因子：
4.1
作者：
O'Brien, Andrew J.;Villani, Linda A.;Steinberg, Gregory R.
通讯作者：
Steinberg, Gregory R.
影响因子：
4.8
作者：
Fryer, LGD;Parbu-Patel, A;Carling, D
通讯作者：
Carling, D