Neferine modulates IGF-1R/Nrf2 signaling in doxorubicin treated H9c2 cardiomyoblasts

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.