The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration

• Published in: Molecular metabolism (Germany) Vol. 5; no. 10; pp. 1048 - 1056
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Germany Elsevier 01.10.2016
• Subjects: Brief Communication; Endocrinology & Metabolism; Lung cancer; oxygen consumption rate; 5′-adenosine monophosphate-activated protein kinase; acetyl-CoA carboxylase; adenoviral control; β1KO; ACC double knock-in (Ser79/212 Ala); Glucose uptake; Colon cancer; Cancer metabolism; FBS; mTOR; ACCDKI; Lipogenesis; adenoviral alpha-1 dominant negative; mammalian target of rapamycin complex 1; AMPK β1-subunit knockout; PBS; ACC; SGLT2; SGLT1; extracellular acidification rate; sodium-glucose transporter 2; 2-DG; Breast cancer; sodium-glucose transporter 1; AD-AMPKDN; 2-deoxy- d-glucose; ECAR; fetal bovine serum; AD-CRE; phosphate buffered saline; AMPK; Prostate cancer; mTORC1; AMP-activated protein kinase AMPK; OCR; ACC, acetyl-CoA carboxylase; OCR, oxygen consumption rate; FBS, fetal bovine serum; PBS, phosphate buffered saline; ACCDKI, ACC double knock-in (Ser79/212 Ala); AMPK, 5′-adenosine monophosphate-activated protein kinase; SGLT2, sodium-glucose transporter 2; 2-DG, 2-deoxy-d-glucose; mTORC1, mammalian target of rapamycin complex 1; SGLT1, sodium-glucose transporter 1; ECAR, extracellular acidification rate; β1KO, AMPK β1-subunit knockout; AD-AMPKDN, adenoviral alpha-1 dominant negative; AD-CRE, adenoviral control
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2016.08.014

Abstract Objective 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. Methods 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. Results 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. Conclusion 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.