Disulfiram and Its Copper Chelate Attenuate Cisplatin-Induced Acute Nephrotoxicity in Rats Via Reduction of Oxidative Stress and Inflammation

Shraddha I. Khairnar, Umesh B. Mahajan, Kalpesh R. Patil, Harun M. Patel, Sachin D. Shinde, Sameer N. Goyal, Sateesh Belemkar, Shreesh Ojha, Chandragouda R. Patil

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

The use of cisplatin (CP) in chemotherapy of resistant cancers is limited due to its dose-dependent nephrotoxicity. Disulfiram (DSF), the aversion therapy for alcoholism, has recently emerged as an anticancer and chemopreventive agent. Its anticancer activity is potentiated in the presence of copper. However, such use of copper leads to several adverse effects. In the present study, the protective effect of DSF and its copper chelate (Cu-DEDC) against CP-induced nephrotoxicity in rats was evaluated. Nephrotoxicity was induced by a single intraperitoneal injection of CP (5 mg/kg). The treatment groups included control (vehicle treated), CP (CP-treated), CP + DSF (CP followed by DSF), CP + DSF + Cu (CP followed by DSF and CuCl2), CP + Cu-DEDC (CP followed by Cu-DEDC), and CP + AMF (amifostine pre-treated and CP-treated). The DSF, Cu-DEDC, and CuCl2 were administered orally at 50 mM/kg/day dose for 5 days post CP injection. AMF served as a standard chemo protectant, administered intravenously 30 min prior to CP. The markers of oxidative stress, inflammation, and kidney function estimated on the 6th day revealed that both DSF and Cu-DEDC significantly attenuated the CP-induced rise in the serum/urine creatinine and blood urea nitrogen (BUN). The CP-induced rise in serum alkaline phosphatase (ALPase) was reversed by these drugs. Both drugs reduced the levels of malondialdehyde and nitric oxide (NO) in kidney tissues. These drugs reversed CP-induced depletion of SOD, catalase, and GSH in the kidneys. There was a significant reduction in the CP-induced TNF-α and IL-1β production along with prevention of histological alterations. Above observations indicate that DSF and Cu-DEDC may have significance as adjuvants to protect against CP-induced nephrotoxicity.

Original languageEnglish
Pages (from-to)174-184
Number of pages11
JournalBiological Trace Element Research
Volume193
Issue number1
DOIs
Publication statusPublished - Jan 1 2020

Keywords

  • Cisplatin
  • Cu-DEDC
  • Cucl
  • Cytokines
  • Disulfiram
  • Nephrotoxicity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Clinical Biochemistry
  • Biochemistry, medical
  • Inorganic Chemistry

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