Uptake Of Biguanides In Mitochondria Appears To Be Related To Increased Glucose Uptake And Medium Acidification But Not Necessarily Related To Inhibition Of Growth Of Bladder And Colon Cancer Cells
Cancer Research(2018)
Abstract
Abstract Biguanides including metformin have been used in the treatment of Type 2 diabetes and they are under investigation as anti-cancer agents. Investigation on the mechanism of action of biguanides has largely focused on inhibition of complex 1 in the mitochondrial electron transport chain with subsequent activation of AMP-dependent protein kinase. Studies by Bridges et al. (BMC Biology 14:65, 2016) indicate that inhibitory effects on complex 1 in cells require uptake of biguanides into the mitochondria. In the present work the action of two biguanides that enter the mitochondria (buformin and phenformin) were compared with the action of two biguanides with poor uptake (phenyl biguanide and proguanil). Effects on growth, glucose uptake and medium acidification were studied with two human colon cancer cells (Caco-2 and HT29) and seven bladder cancer cell lines (5637, HT1197, HT1376, RT4, T24, TCCSUP and UM-UC-3). After incubation for 72 hours with 25 µM and 50 µM concentrations of the biguanides, growth inhibition was greatest with proguanil followed by phenformin and with little or no growth inhibition at these concentrations with buformin and phenylbiguanide. In contrast, increased glucose uptake and acidification of the medium was observed with buformin and phenformin with no change or decreased medium acidification with phenyl biguanide and proguanil. Studies with buformin over a concentration range from 10 µM to 500 µM indicated that there was generally growth inhibition at concentrations greater than 50 µM. Studies on medium acidification and glucose uptake revealed biphasic responses with increases at lower concentrations that were reversed at higher concentrations of buformin where growth inhibition was observed. The data suggested that the effect of biguanides on glucose metabolism requires mitochondrial uptake while the mechanism for growth inhibition by biguanides remains to be established. Citation Format: Michael A. Lea, Haneulsol Kim, Charles desBordes. Uptake of biguanides in mitochondria appears to be related to increased glucose uptake and medium acidification but not necessarily related to inhibition of growth of bladder and colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 381.
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Key words
glucose uptake,mitochondria,biguanides,cancer cells
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