Forskolin attenuates doxorubicin-induced accumulation of asymmetric dimethylarginine and s-adenosylhomocysteine via methyltransferase activity in leukemic monocytes

Publication date: 2018Source: Leukemia Research Reports, Volume 9Author(s): Sandhiya Ramachandran, Swetha Loganathan, Vinnie Cheeran, Soniya Charles, Ganesh Munuswamy-Ramanujan, Mohankumar Ramasamy, Vijay Raj, Kanchana MalaAbstractDoxorubicin (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.Graphical abstractPossible signal pathway by which forskolin regulates arginine methylation. Forskolin prevents doxorubicin-induced methyltransferase activity which mitigates biosynthesis of ADMA and SAH, the intermediate products of protein methylation. ADMA is an endogenous inhibitor of eNOS which catalyses the formation of nitric oxide. Hence, an increase in intracellular or circulating ADMA concentration l...
Source: Leukemia Research Reports - Category: Hematology Source Type: research