Investigating and targeting chronic lymphocytic leukemia metabolism with the human immunodeficiency virus protease inhibitor ritonavir and metformin.
Chronic lymphocytic leukemia (CLL) remains fatal due to the development of resistance to existing therapies. Targeting abnormal glucose metabolism sensitizes various cancer cells to chemotherapy and/or elicits toxicity. Examination of glucose dependency in CLL demonstrated variable sensitivity to glucose deprivation. Further evaluation of metabolic dependencies of CLL cells resistant to glucose deprivation revealed increased engagement of fatty acid oxidation upon glucose withdrawal. Investigation of glucose transporter expression in CLL reveals up-regulation of glucose transporter GLUT4. Treatment of CLL cells with human immunodeficiency (HIV) protease inhibitor ritonavir, which inhibits GLUT4, elicits toxicity similar to that elicited upon glucose deprivation. CLL cells resistant to ritonavir are sensitized by co-treatment with metformin, potentially targeting compensatory mitochondrial complex 1 activity. Ritonavir and metformin have been administered in humans for the treatment of diabetes in patients with HIV, demonstrating the tolerance to this combination in humans. Our studies strongly substantiate further investigation of Food and Drug Administration approved ritonavir and metformin for CLL.
University of Texas M. D. Anderson Cancer Center , Houston, TX , USA.
Kehinde U A
KU
Adekola
Sevim
S
Dalva Aydemir
Shuo
S
Ma
Zheng
Z
Zhou
Steven T
ST
Rosen
Mala
M
Shanmugam
D000368:Aged; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D019438:Ritonavir / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D051275:Glucose Transporter Type 4; D017320:HIV Protease Inhibitors; D007004:Hypoglycemic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D008687:Metformin; D005947:Glucose; D019438:Ritonavir
Basic biology; chemotherapeutic approaches; lymphoid leukemia; signal transduction