Metformin is a commonly prescribed drug for metabolic disorders particularly in type 2 diabetes. In addition to Metformin’s established antidiabetic effect it has a potential for use as an anti-cancer medication, via mitochondrial complex inhibition.

Methods: In order to determine what effect Metformin could have on a common cancer such as lymphoma at a cellular level, we performed a 14 day experiment on the effect of 3 different doses of Metformin (0mM, 0.025mM, 0.25mM) on two different lymphoid cell lines, Jurkat and Jeko. Metformin at 0.025mM, is considered physiological. Cells in culture were collected on Days 3, 7, 10, and 14 and RT-PCR targeted gene expression was carried out focusing on mitochondrial and apoptosis related genes such as cytochrome oxidases (COX2 and 4), nuclear respiratory factor (NRF1), apoptosis gene (P53) and other mitochondrial genes such as PGC1A, SOD2, and TFAM.

Results: Jeko cells showed initial significant mitochondrial gene suppression with Metformin. The suppression in mRNA gene expression however appear to reverse by day 7. By Day 10 there is a uniform up-regulation in mRNA expressions and the effects stabilized by day 14. Our Jurkat cells showed less consistent mRNA level changes, though the pattern was similar.

In summary, Jeko cells, upon initial exposure to Metformin, show a decrease in mitochondrial biogenesis and increased apoptosis. This initial suppression seems to be replaced by over-expression of mitochondrial genes over a period of time and its effects stabilizes by day 10 of exposure. This phenomenon appears to be shown in both cell lines. We plan to corroborate our gene expression findings with Sea-Horse cell respiration studies.

Conclusion: We believe that Metformin initially causes cancer cell damage, however with time the cells are able to escape that phenomenon by up-regulating mitochondrial genes particularly at physiological doses. In order for Metformin to be an effective pro-apoptotic agent in a cancer scenario, brief pulses of supra-physiological doses may be more effective.

Disclosure

N. Ahmadi: None. S. Sen: None.

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