Abstract
Occurrence of oxidative stress is the principal cause of acute kidney injury induced by cisplatin. Mangiferin, a naturally occurring antioxidant molecule, is found to ameliorate several oxidative stress mediated pathophysiological conditions including cancer. Cisplatin induced cytotoxicity was measured in NKE cells by MTT assay and microscopic analysis. Induction of oxidative stress and regulation of proapoptotic molecules were subsequently investigated by using different spectrophotometric analyses, FACS and immunocytochemistry. Induction of nephrotoxicity was determined by analyzing different serum biomarkers and histological parameters in vivo using swiss albino mice. Activation of NF-κB mediated pro-inflammatory and caspase dependent signaling cascades were investigated by semi-quantitative RT-PCR and immunoblotting. Mangiferin was found to ameliorate cisplatin induced nephrotoxicity in vitro and in vivo by attenuating the induction of oxidative stress and upregulating Nrf-2 mediated pro-survival signaling cascades via the activation of PI3K. Additionally, mangiferin showed synergistic anticancer activity with cisplatin in cancer cell lines (MCF-7 and SKRC-45) and EAC cell induced solid tumor bearing experimental mice. The ameliorative effect of mangiferin is primarily attributed to its anti-oxidant and anti-inflammatory properties. It acts differentially in normal tissue cells and tumor cells by modulating different cell survival regulatory signaling molecules. For the first time, the study reveals a mechanistic basis of mangiferin action against cisplatin induced nephrotoxicity. Since Mangiferin shows synergistic anticancer activity with cisplatin, it can be considered as a promising drug candidate, to be used in combination with cisplatin.
Highlights
Cisplatin, cis-diamminedichloroplatinum (II), is a widely used anticancer drug and is effective against several types of cancers in almost all parts of the body, including cancers of the breast, lung, ovary, testis, head, and neck
Different reports suggest that elevated level of inflammatory cytokines and intracellular reactive oxygen species (ROS) mediated mechanisms are involved with the acute kidney injury (AKI) associated cytotoxicity (Burmeister et al, 2017)
Our results showed that mangiferin can significantly inhibit the induction of oxidative stress by cisplatin in normal kidney epithelial (NKE) cells and cellular death
Summary
Cis-diamminedichloroplatinum (II), is a widely used anticancer drug and is effective against several types of cancers in almost all parts of the body, including cancers of the breast, lung, ovary, testis, head, and neck. The cisplatin induced nephrotoxicity was first reported 30 years ago and thereafter several studies have been undertaken to elucidate the molecular mechanism underlying cisplatin induced diseased condition in the renal tissue (Kodama et al, 2014; Potocnjak and Domitrovic, 2016). Extensive research has been done with these bioactive molecules to identify complementary and alternative medicines (Manna et al, 2007; Das et al, 2009; Chowdhury et al, 2016; Ghosh et al, 2016; Sarkar et al, 2016) These molecules have been found to be effective against several pathophysiological conditions and interestingly these natural molecules show no significant harmful effects in dietary doses. Studying the effects of different natural compounds against cisplatin induced kidney dysfunction is perceived to be significant (Sarkar and Sil, 2006; Pal et al, 2011; Tamadon et al, 2014; Yang et al, 2016a)
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