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 18F-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.
Highlights
Observations that metformin (1,1-dimethylbiguanide), the most commonly prescribed drug for type II diabetes reduces cancer risk have promoted an enthusiasm for metformin as an anti-cancer therapy [1,2]
Phenformin was withdrawn from clinical use in many countries in the late 1970s when an association with lactic acidosis and several fatal case reports was recognized [5]
Most available data relating to the effects of biguanides on cancer cells, and our own previous work [21,22,23], have concerned metformin
Summary
Observations that metformin (1,1-dimethylbiguanide), the most commonly prescribed drug for type II diabetes reduces cancer risk have promoted an enthusiasm for metformin as an anti-cancer therapy [1,2]. Clinical trials in breast cancer using metformin alone or in combination with other therapies are underway [3,4]. Phenformin, another biguanide (1-phenethylbiguanide) was introduced at the same time as metformin, in the late 1950s as an anti-diabetic drug. Phenformin is nearly 50 times as potent as metformin but was associated with a higher incidence of lactic acidosis, a major side effect of biguanides. Phenformin was withdrawn from clinical use in many countries in the late 1970s when an association with lactic acidosis and several fatal case reports was recognized [5]. The effect of phenformin on cancer has rarely been studied
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