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

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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.

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Authors and Affiliations

  1. Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dist. Dhule, Maharashtra, 425405, India

    Shraddha I. Khairnar, Umesh B. Mahajan, Sachin D. Shinde, Sameer N. Goyal & Chandragouda R. Patil

  2. Department of Pharmacology, H. R. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dist. Dhule, Maharashtra, 425405, India

    Kalpesh R. Patil

  3. Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dist. Dhule, Maharashtra, 425405, India

    Harun M. Patel

  4. Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule, Maharashtra, 424001, India

    Sameer N. Goyal

  5. Department of Pharmacology, School of Pharmacy & Technology Management, SVKM’s NMIMS, Shirpur, India, Shirpur, Dist. Dhule, Maharashtra, 425405, India

    Sateesh Belemkar

  6. Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, Abu Dhabi, United Arab Emirates

    Shreesh Ojha

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  1. Shraddha I. Khairnar
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Correspondence to Chandragouda R. Patil.

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Experimental procedures involving the use of laboratory animals were approved (protocol approval no. IAEC/CPCSEA/RCPIPER/2017-15) by the Institutional Animal Ethics Committee (IAEC) of the R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dist. Dhule (M.S.), India (reg. no. 651/PO/ReBi/S/02/CPCSEA) constituted under the “Prevention of Cruelty to the Animals Act- 1960.” All the experiments were carried out according to the guidelines prescribed by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India.

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Khairnar, S.I., Mahajan, U.B., Patil, K.R. et al. Disulfiram and Its Copper Chelate Attenuate Cisplatin-Induced Acute Nephrotoxicity in Rats Via Reduction of Oxidative Stress and Inflammation. Biol Trace Elem Res 193, 174–184 (2020). https://doi.org/10.1007/s12011-019-01683-w

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