Synergistic anti-cancer effect of phenformin and oxamate.
Phenformin (phenethylbiguanide; an anti-diabetic agent) plus oxamate [lactate dehydrogenase (LDH) inhibitor] was tested as a potential anti-cancer therapeutic combination. In in vitro studies, phenformin was more potent than metformin, another biguanide, recently recognized to have anti-cancer effects, in promoting cancer cell death in the range of 25 times to 15 million times in various cancer cell lines. The anti-cancer effect of phenformin was related to complex I inhibition in the mitochondria and subsequent overproduction of reactive oxygen species (ROS). Addition of oxamate inhibited LDH activity and lactate production by cells, which is a major side effect of biguanides, and induced more rapid cancer cell death by decreasing ATP production and accelerating ROS production. Phenformin plus oxamate was more effective than phenformin combined with LDH knockdown. In a syngeneic mouse model, phenformin with oxamate increased tumor apoptosis, reduced tumor size and (18)F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography compared to control. We conclude that phenformin is more cytotoxic towards cancer cells than metformin. Furthermore, phenformin and oxamate have synergistic anti-cancer effects through simultaneous inhibition of complex I in the mitochondria and LDH in the cytosol, respectively.
Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, South Dakota, United States of America ; Department of Obstetrics and Gynecology and Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Sioux Falls, South Dakota, United States of America.
W Keith
WK
Miskimins
Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Hyun Joo
HJ
Ahn
Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Ji Yeon
JY
Kim
Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Sun
S
Ryu
Head and Neck Oncology Clinic, Center of Specific Organs Cancer, Center for Thyroid Cancer, Research Institute and Hospital, National Cancer Center, Goyang-si, Gyeonggi-do, Korea.
Yuh-Seog
YS
Jung
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Joon Young
JY
Choi
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004338:Drug Combinations; D004357:Drug Synergism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism; D019788:Fluorodeoxyglucose F18 / Q000008:administration & dosage; D006019:Glycolysis / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009368:Neoplasm Transplantation; D010072:Oxamic Acid / Q000494:pharmacology*; D010629:Phenformin / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D004338:Drug Combinations; D017382:Reactive Oxygen Species; D019788:Fluorodeoxyglucose F18; D000255:Adenosine Triphosphate; D010629:Phenformin; D007770:L-Lactate Dehydrogenase; D042967:Electron Transport Complex I; D010072:Oxamic Acid