Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer

Pancreatic cancer is one of the hardest-to-treat types of neoplastic diseases. Metformin, a widely prescribed drug against type 2 diabetes mellitus, is being trialed as an agent against pancreatic cancer, although its efficacy is low. With the idea of delivering metformin to its molecular target, the mitochondrial complex I (CI), we tagged the agent with the mitochondrial vector, triphe- nylphosphonium group. Mitochondrially targeted metformin (MitoMet) was found to kill a panel of pancreatic cancer cells three to four orders of magnitude more efficiently than found for the parental compound. Respiration assessmentdocumentedCI as the molecular target for MitoMet, which was corroborated by molec- ular modeling. MitoMet also efficiently suppressed pancreatic tumors in three mouse models. We propose that the novel mito- chondrially targetedagent is clinically highly intriguing,andithas a potential to greatly improve the bleak prospects of patients with pancreatic cancer.