Metformin, one of the most widely prescribed
antidiabetic drugs in the world, is being repurposed as a potential drug in
cancer treatment. Epidemiological studies suggest that
metformin exerts anticancer effects in diabetic patients with
pancreatic cancer. However, at typical
antidiabetic doses the bioavailability of
metformin is presumably too low to exert antitumor effects. Thus, more potent analogs of
metformin are needed in order to increase its anticancer efficacy. To this end, a new class of mitochondria-targeted
metformin analogs (or mito-metformins) containing a positively-charged lipophilic
triphenylphosphonium group was synthesized and tested for their antitumor efficacy in
pancreatic cancer cells. Results indicate that the lead compound, mito-metformin10, was nearly 1000-fold more potent than
metformin in inhibiting mitochondrial complex I activity, inducing
reactive oxygen species (
superoxide and
hydrogen peroxide) that stimulate redox signaling mechanisms, including the activation of adenosinemonophosphate
kinase and inhibition of proliferation of
pancreatic cancer cells. The potential use of the low-temperature electron paramagnetic resonance technique in assessing the role of mitochondrial complexes including complex I in
tumor regression in response to
metformin and mito-metformins in the in vivo setting is discussed.