Abstract
Doxorubicin (Dox) is a widely administered chemotherapeutic drug and incidences of cardiotoxicity associated with its administration have been of general concern. Extensive research proposes several mechanisms as a cause of Dox induced cardiotoxicity. However, none of these studies have been able to suggest a find one, cure all antidote for the same. To this end, several studies involving plant based compounds or natural products have gained acclaim for their ability to address at least one factor contributing to drug induced pathogenesis. We had previously reported that p-coumaric (pCA) has a protective effect on Dox induced oxidative stress in rat-derived cardiomyoblasts. In this study we investigated the effects of pCA on the regulation of Nrf-2, mitochondrial viability, autophagy and apoptosis in Doxorubicin treated H9c2 cardiomyocytes. ROS induced mitochondrial stress, changes in mitochondrial membrane potential, loss of membrane integrity; nuclear damage as single/double stranded breaks, autophagy and the effects of pre and co-treatment of pCA on Nrf-2 mediated signaling was evaluated by various approaches. The effect of pCA on drug uptake was evaluated through confocal Raman Spectroscopy. We find that nuclear translocation of Nrf-2 is prominently marked by protein-specific antibody conjugated fluorophore in Dox treated cells especially. Cell survival is mediated to a certain extent by the expression of the anti-apoptotic BCl2 in pCA treated cells. However, mRNA levels of autophagy related (Atg) genes suggest that autophagy plays a decisive role in deciding cellular fate. Caspase-3 activation is also observed in pCA treated cells which suggest an alternative function of caspase-3 in pCA mediated cell survival. Expression of antioxidant enzymes confirm the oxidative stress induced by Dox treatment in cells and the modulation of cell redox homeostasis through treatment with pCA.
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