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


CONCLUSIONS
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.
Department of Medicine, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Linda A
LA
Villani
Department of Medicine, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Brennan K
BK
Smith
Department of Medicine, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Katarina
K
Marcinko
Department of Medicine, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Rebecca J
RJ
Ford
Department of Medicine, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Lindsay A
LA
Broadfield
Department of Medicine, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Alex E
AE
Green
Department of Oncology, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Vanessa P
VP
Houde
Department of Oncology, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Paola
P
Muti
Department of Oncology, McMaster University, Hamilton, Ontario, L8K 4P1, Canada.
Theodoros
T
Tsakiridis
Department of Medicine, McMaster University, Hamilton, Ontario, L8K 4P1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, L8K 4P1, Canada. Electronic address: gsteinberg@mcmaster.ca.
Gregory R
GR
Steinberg
2-DG, 2-deoxy-d-glucose; ACC, acetyl-CoA carboxylase; ACCDKI, ACC double knock-in (Ser79/212 Ala); AD-AMPKDN, adenoviral alpha-1 dominant negative; AD-CRE, adenoviral control; AMP-activated protein kinase AMPK; AMPK, 5′-adenosine monophosphate-activated protein kinase; Breast cancer; Cancer metabolism; Colon cancer; ECAR, extracellular acidification rate; FBS, fetal bovine serum; Glucose uptake; Lipogenesis; Lung cancer; OCR, oxygen consumption rate; PBS, phosphate buffered saline; Prostate cancer; SGLT1, sodium-glucose transporter 1; SGLT2; SGLT2, sodium-glucose transporter 2; mTOR; mTORC1, mammalian target of rapamycin complex 1; β1KO, AMPK β1-subunit knockout
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