Regucalcin ameliorates doxorubicin-induced cytotoxicity in Cos-7 kidney cells and translocates from the nucleus to the mitochondria.

Noor A Mohammed,Israa J Hakeem,Francesco Michelangeli,Nikolas Hodges

doi:10.1042/bsr20211464

Noor A Mohammed, Israa J Hakeem + Show 2 more

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https://doi.org/10.1042/bsr20211464

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Abstract

Doxorubicin (DOX) is a potent anticancer drug, which can have unwanted side-effects such as cardiac and kidney toxicity. A detailed investigation was undertaken of the acute cytotoxic mechanisms of DOX on kidney cells, using Cos-7 cells as kidney cell model. Cos-7 cells were exposed to DOX for a period of 24 h over a range of concentrations, and the LC50 was determined to be 7 µM. Further investigations showed that cell death was mainly via apoptosis involving Ca2+ and caspase 9, in addition to autophagy. Regucalcin (RGN), a cytoprotective protein found mainly in liver and kidney tissues, was overexpressed in Cos-7 cells and shown to protect against DOX-induced cell death. Subcellular localization studies in Cos-7 cells showed RGN to be strongly correlated with the nucleus. However, upon treatment with DOX for 4 h, which induced membrane blebbing in some cells, the localization appeared to be correlated more with the mitochondria in these cells. It is yet to be determined whether this translocation is part of the cytoprotective mechanism or a consequence of chemically induced cell stress.

Highlights

Doxorubicin (DOX) is a potent anticancer drug, which consists of an amino-sugar daunosamine bound to a tetracycline moiety [1]
In order to assess whether DOX induces necrosis, lactate dehydrogenase (LDH) release form Cos-7 cells treated with DOX was undertaken
We found that cell death of Cos-7 kidney cells by DOX mainly occurred through apoptosis

Summary

Introduction

Doxorubicin (DOX) is a potent anticancer drug, which consists of an amino-sugar daunosamine bound to a tetracycline moiety [1]. DOX has been shown to affect mitochondrial function and cause elevation of reactive oxygen species [3]. Nephrotoxicity is one of the more notable side-effects of anthracycline antibiotics such as DOX [1,5] and can limit its uses in some patients that show renal impairment. As such an investigation into its mechanisms of cytotoxicity in kidney cells, as well as identifying approaches that can reduce this nephrotoxicity, would be of potential clinical relevance

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