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Doxorubicin (DOX) mediated cardiomyopathy is a major challenge in cancer chemotherapy. Redox-cycling of doxorubicin by flavoenzymes makes the heart more vulnerable to oxidative stress leading to cardiac dysfunction. The present study evaluates the role of neferine, a bisbenzylisoquinoline alkaloid, in curbing the molecular consequences of DOX-exposure in H9c2 cardiomyoblasts. Neferine pre-treatment increased cell viability upon DOX-exposure. DOX activates NADPH oxidase subunits, (p22phox, p47phox, gp91phox) as the primary event followed by peak in [Ca2+]i accumulation by 2 h, ROS by 3 h and activated ERK1/2 and p38 MAPKinases, time dependently along with the activation and translocation of NFκB and up-regulated COX2 and TNF-α expressions. Neferine pre-treatment modulated NADPH oxidase/ROS system, inhibited MAPKinases and NFκB activation, reduced sub G1 cell population and concomitantly increased cyclin D1 expression reducing DOX-mediated apoptosis. The study demonstrates for the first time, the molecular sequential events behind DOX toxicity and the mechanism of protection offered by neferine with specific relevance to NADPH oxidase system, MAPKinases, inflammation and apoptosis in H9c2 cells. Our data suggests the use of neferine as a new approach in pharmacological interventions against cardiovascular disorders as secondary complications.

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Doxorubicin (DOX) induced cardiotoxicity is a major problem during chemotherapy of cancers. DOX-mediated suppression of type 1 IGF receptor (IGF-1R) signaling leads to cardiac dysfunction. Neferine, a bisbezylisoquinoline alkaloid from the seed embryos of Nelumbo nucifera Gaertn possesses a distinct range of pharmacological properties. Herewith, the present study attempts to elucidate the protective role of neferine against DOX induced toxicity in H9c2 rat cardiomyoblast cell line model. DOX-treated H9c2 cells significantly increased mitochondrial superoxide generation, depleted cellular antioxidant status, suppressed the activation of IGF-1R signaling via PI3K/Akt/mTOR and induced autophagy by the activation of ULK1, Beclin1, Atg7, and LC3B. Neferine pre-treatment activated IGF-1R signaling, improved cellular antioxidant pool, increased the expression of down-stream targets of IGF-1R, such as PI3K/Akt/mTOR, inhibited mitochondrial superoxide generation and autophagy significantly with the induction of Nrf2 translocation and expressions of HO1 and SOD1. Our study suggests the use of neferine for amelioration of DOX-mediated cardiotoxicity.