Fathima  S. Ameer,Xiaomin  Zhang,Gohar  Azhar,Yingni  Che,Jeanne  Y. Wei,
Low Glucose Enhances the Cytoprotective Effect of Metformin Against Doxorubicin Induced Cytotoxicity in Normal Cells
Journal of Diabetes Metabolism and its Complications
2020
2674-4163
http://dx.doi.org/10.31487/j.JDMC.2020.01.04
https://www.sciencerepository.org/low-glucose-enhances-the-cytoprotective-effect-of-metformin-against-doxorubicin_JDMC-2020-1-104 
Abstract: The anti-diabetic drug, metformin, has been reported to be beneficial for the cardiovascular system and
may facilitate the extension of a healthier lifespan. Doxorubicin is a leading chemotherapeutic drug used
to treat a variety of cancers, yet it can cause significant adverse effects with cardiac toxicity and longterm damage. To test the hypothesis that the hypoglycaemic agent, metformin, may protect normal cells
during chemotherapy treatment with liposomal doxorubicin, C2C12 myoblast cells were used to study
cellular bioenergetics, variations in gene expressions and biochemical alterations induced by metformin
and pegylated liposomal doxorubicin (L-Doxo) under low glucose conditions (2.7 mM or 50 mg/dL).
Using confocal microscopy, we noted that treatment of C2C12 cells with 30 µg/mL L-Doxo under low
glucose conditions induced a number of cellular defects. L-Doxo treatment dysregulated the expression
of mitochondrial fission and fusion genes, which may influence transformation of the network’s
connectivity. L-Doxo significantly reduced mitochondrial oxygen consumption rate (OCR) and
extracellular acidification rate (ECAR). However, pre-treatment of cells with 100 nM metformin
provided protection against L-Doxo-induced damage and increased cell viability and ATP levels in cells
even under low glucose conditions. In addition, metformin increased and restored the decreased OCR
and ECAR. Our data provide a mechanism by which low dose metformin exerts protective effects against
L-Doxo via involvement of AMPKα under low glucose conditions. Taken together, our results
demonstrate that metformin protects normal cells from L-Doxo damage even under low glucose
conditions.Keywords: Metformin, L-Doxo, Low glucose, Mitochondrial protection, Cancer