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15357163mct151021-sup-160318_2_supp_3643457_jcjcbb.doc (211 kB)

Supplementary methods from Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer

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posted on 2023-04-03, 15:46 authored by Stepana Boukalova, Jan Stursa, Lukas Werner, Zuzana Ezrova, Jiri Cerny, Ayenachew Bezawork-Geleta, Alena Pecinova, Lanfeng Dong, Zdenek Drahota, Jiri Neuzil

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Australian Research Council

Czech Ministry of Health

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ARTICLE ABSTRACT

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, triphenylphosphonium 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 assessment documented CI as the molecular target for MitoMet, which was corroborated by molecular modeling. MitoMet also efficiently suppressed pancreatic tumors in three mouse models. We propose that the novel mitochondrially targeted agent is clinically highly intriguing, and it has a potential to greatly improve the bleak prospects of patients with pancreatic cancer. Mol Cancer Ther; 15(12); 2875–86. ©2016 AACR.

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