Doxorubicin (DOX) is an antitumor drug, associated with cardiomyopathy. Strategies to address DOX-cardiomyopathy are scarce. Here, we identify the effect of forskolin (FSK) on DOX-induced-asymmetric-dimethylarginine (ADMA) accumulation in monocytoid cells. DOX-challenge led to i) augmented cytotoxicity, reactive-oxygen-species (ROS) production and methyltransferase-enzyme-activity identified as ADMA and s-adenosylhomocysteine (SAH) accumulation (SAH-A). However, except cytotoxicity, other DOX effects were decreased by metformin and FSK. FSK, did not alter the DOX-induced cytotoxic effect, but, decreased SAH-A by >50% and a combination of three drugs restored physiological methyltransferase-enzyme-activity. Together, protective effect of FSK against DOX-induced SAH-A is associated with mitigated methyltransferase-activity, a one-of-a-kind report.
Keywords: ADMA, asymmetric dimethylarginine; CT, chemotherapy; CVD, cardiovascular disease; Cancer; Cardiovascular disease; DDAH, dimethylarginine diaminohydrolase; DOX, doxorubicin; Endothelial dysfunction; FSK, forskolin; Forskolin; HCY, homocysteine; HTRF, homogenous time-resolved fluorescence; L-arg, L-arginine; L-cit, L-citrulline; MET, metformin; Metformin; Methyltransferase; NAD+, nicotinamide adenine dinucleotide; OS, oxidative stress; PRMT1, protein arginine methyltransferase1; ROS, reactive oxygen species; SAH, s-adenosylhomocysteine;; SAH-A, SAH accumulation; SAHH, s-adenosylhomocysteine hydrolase; SAM, s-adenosylmethionine; SIRT1, sirtuin1; cAMP, cyclic AMP; eNOS, endothelial nitric oxide synthase.