Biguanides sensitize leukemia cells to ABT-737-induced apoptosis by inhibiting mitochondrial electron transport.
Metformin displays antileukemic effects partly due to activation of AMPK and subsequent inhibition of mTOR signaling. Nevertheless, Metformin also inhibits mitochondrial electron transport at complex I in an AMPK-independent manner, Here we report that Metformin and rotenone inhibit mitochondrial electron transport and increase triglyceride levels in leukemia cell lines, suggesting impairment of fatty acid oxidation (FAO). We also report that, like other FAO inhibitors, both agents and the related biguanide, Phenformin, increase sensitivity to apoptosis induction by the bcl-2 inhibitor ABT-737 supporting the notion that electron transport antagonizes activation of the intrinsic apoptosis pathway in leukemia cells. Both biguanides and rotenone induce superoxide generation in leukemia cells, indicating that oxidative damage may sensitize toABT-737 induced apoptosis. In addition, we demonstrate that Metformin sensitizes leukemia cells to the oligomerization of Bak, suggesting that the observed synergy with ABT-737 is mediated, at least in part, by enhanced outer mitochondrial membrane permeabilization. Notably, Phenformin was at least 10-fold more potent than Metformin in abrogating electron transport and increasing sensitivity to ABT-737, suggesting that this agent may be better suited for targeting hematological malignancies. Taken together, our results suggest that inhibition of mitochondrial metabolism by Metformin or Phenformin is associated with increased leukemia cell susceptibility to induction of intrinsic apoptosis, and provide a rationale for clinical studies exploring the efficacy of combining biguanides with the orally bioavailable derivative of ABT-737, Venetoclax.
Grupo de Terapia Celular y Molecular, Pontificia Universidad Javeriana, Bogotá, Colombia.|Programa de Investigación e Innovación en Leucemia Aguda y Crónica (PILAC), Bogotá, Colombia.
Juliana
J
Velez
Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Rongqing
R
Pan
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
Jason T C
JT
Lee
Programa de Investigación e Innovación en Leucemia Aguda y Crónica (PILAC), Bogotá, Colombia.
Leonardo
L
Enciso
Programa de Investigación e Innovación en Leucemia Aguda y Crónica (PILAC), Bogotá, Colombia.
Marta
M
Suarez
Centro Oncológico de Antioquia, Medellín, Colombia.
Jorge Eduardo
JE
Duque
Grupo de Terapia Celular y Molecular, Pontificia Universidad Javeriana, Bogotá, Colombia.
Daniel
D
Jaramillo
Grupo de Terapia Regenerativa, Universidad de Caldas, Manizales, Colombia.
Catalina
C
Lopez
Grupo de Terapia Celular y Molecular, Pontificia Universidad Javeriana, Bogotá, Colombia.
Ludis
L
Morales
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
William
W
Bornmann
Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Marina
M
Konopleva
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
Gerald
G
Krystal
Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Michael
M
Andreeff
Grupo de Terapia Celular y Molecular, Pontificia Universidad Javeriana, Bogotá, Colombia.|Programa de Investigación e Innovación en Leucemia Aguda y Crónica (PILAC), Bogotá, Colombia.|Centre for Drug Research and Development, Vancouver, Canada.
Ismael
I
Samudio
D017209:Apoptosis / Q000187:drug effects*; D001645:Biguanides / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004579:Electron Transport / Q000187:drug effects*; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology*; D010629:Phenformin / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D020298:U937 Cells
C501332:ABT-737; D001645:Biguanides; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D012402:Rotenone; D008687:Metformin; D010629:Phenformin; C579720:venetoclax
ABT 737; leukemia; metformin; mitochondria; phenformin