Villani Linda A, Smith Brennan K, Marcinko Katarina, Ford Rebecca J, Broadfield Lindsay A, Green Alex E, Houde Vanessa P, Muti Paola, Tsakiridis Theodoros, Steinberg Gregory R
Department of Medicine, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Department of Oncology, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Mol Metab. 2016 Aug 26;5(10):1048-1056. doi: 10.1016/j.molmet.2016.08.014. eCollection 2016 Oct.
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.
钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂卡格列净和达格列净是最近被批准用于治疗2型糖尿病的药物。最近的研究表明，SGLT2抑制剂可能会抑制某些癌细胞的生长，但其机制尚不清楚。
采用细胞增殖和克隆形成存活率来评估前列腺癌和肺癌细胞生长对SGLT2抑制剂的敏感性。评估了氧气消耗、细胞外酸化率、细胞ATP、葡萄糖摄取、脂肪生成以及AMP激活蛋白激酶（AMPK）、乙酰辅酶A羧化酶和p70S6激酶的磷酸化情况。使用维持复合体I支持线粒体呼吸的蛋白质（NDI1）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。
临床可达到的卡格列净浓度，而非达格列净浓度，单独以及与电离辐射和化疗药物多西他赛联合使用时，均可抑制前列腺癌和肺癌细胞的细胞增殖和克隆形成存活率。卡格列净降低了葡萄糖摄取、线粒体复合体I支持的呼吸、ATP和脂肪生成，同时增加了AMPK的激活磷酸化。NDI1的过表达阻断了卡格列净的抗增殖作用，表明线粒体呼吸的降低对于抗增殖作用至关重要。
这些数据表明，与双胍类药物二甲双胍一样，卡格列净不仅能降低血糖，还能抑制前列腺癌和肺癌细胞中线粒体复合体I支持的呼吸和细胞增殖。这些观察结果支持开展研究，评估卡格列净在临床前动物模型中限制肿瘤发生的临床疗效，以及在临床人群中开展关于癌症发病率相对于其他降糖疗法的流行病学研究。
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