Nicotine Exposure Augments Renal Toxicity of 5-aza-cytidine Through p66shc: Prevention by Resveratrol

Istvan Arany; Samuel Hall; Amir Faisal; Mehul Dixit

doi:10.21873/anticanres.11793

Nicotine Exposure Augments Renal Toxicity of 5-aza-cytidine Through p66shc: Prevention by Resveratrol

Anticancer Res. 2017 Aug;37(8):4075-4079. doi: 10.21873/anticanres.11793.

Authors

Istvan Arany¹, Samuel Hall², Amir Faisal³, Mehul Dixit²

Affiliations

¹ Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, U.S.A. iarany@umc.edu.
² Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, U.S.A.
³ Lahore University of Management Sciences, Lahore, Pakistan.

PMID: 28739690
DOI: 10.21873/anticanres.11793

Abstract

Background/aim: We have shown that either chronic nicotine (NIC) exposure or 5-aza-cytidine (AZA) augments oxidative stress-dependent injury through stimulating p66shc in renal cells. Hence, NIC could exacerbate adverse effects of AZA while antioxidants such as resveratrol (RES) could prevent it.

Materials and methods: Renal proximal tubule cells (NRK52E) were treated with 20 μM RES prior to 200 μM NIC plus 100 nM AZA and cell injury (LDH release) was determined. Reporter luciferase assays determined p66shc activation and RES-induced antioxidant responses. Genetic manipulations identified the mechanism of RES action.

Results: NIC exacerbated AZA-dependent injury via augmenting p66shc transcription. While RES suppressed NIC+AZA-mediated injury, -surprisingly-it further enhanced activity of the p66shc promoter. RES protected cells via the cytoplasmic p66shc/Nrf2/heme oxygenase-1 (HO-1) axis.

Conclusion: RES can protect the kidney from adverse effects of NIC in patients undergoing anticancer therapy.

Keywords: 5-aza-cytidine; nicotine; p66shc; renal-toxicity; resveratrol.

MeSH terms

Antioxidants / administration & dosage
Azacitidine / adverse effects
Cell Line
Heme Oxygenase-1 / genetics
Humans
Kidney Tubules, Proximal / drug effects*
Kidney Tubules, Proximal / injuries
Kidney Tubules, Proximal / pathology
NF-E2-Related Factor 2 / genetics
Neoplasms / complications*
Neoplasms / drug therapy
Neoplasms / pathology
Nicotine / adverse effects
Oxidative Stress / drug effects
Promoter Regions, Genetic
Resveratrol
Signal Transduction / drug effects
Src Homology 2 Domain-Containing, Transforming Protein 1 / biosynthesis*
Src Homology 2 Domain-Containing, Transforming Protein 1 / genetics
Stilbenes / administration & dosage*

Substances

Antioxidants
NF-E2-Related Factor 2
NFE2L2 protein, human
SHC1 protein, human
Src Homology 2 Domain-Containing, Transforming Protein 1
Stilbenes
Nicotine
HMOX1 protein, human
Heme Oxygenase-1
Azacitidine
Resveratrol