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PLoS One. 2014 Jan 21;9(1):e85576. doi: 10.1371/journal.pone.0085576. eCollection 2014.

Synergistic anti-cancer effect of phenformin and oxamate.

Author information

1
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.
2
Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
3
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.
4
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Abstract

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.

PMID:
24465604
PMCID:
PMC3897486
DOI:
10.1371/journal.pone.0085576
[Indexed for MEDLINE]
Free PMC Article

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