title: Raloxifene Inhibits NF-kB Pathway and Potentiates Anti-Tumour Activity of Cisplatin with Simultaneous Reduction in its Nephrotoxictiy.
abstract: Cisplatin induced nephrotoxicity is the chief obstacle in the use of cisplatin as chemotherapeutic agent. However, it remains as most widely employed anticancer agent to treat various solid tumours like head-neck, testicular, ovarian and mammary gland cancer. Raloxifene is claimed to be potent anti-inflammatory as well as anti-cancer agent. The present study was carried out to explore the effect of pre-treatment of raloxifene on cisplatin induced nephrotoxicity and its anti-tumour activity in 7, 12 dimethyl benz [a] anthracene induced mammary tumour in animal model. Renal damage was accessed by measuring serum level of creatinine, blood urea nitrogen and albumin whereas systemic inflammation was accessed by measuring level of pro-inflammatory cytokines like tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 10 (IL-10) and nuclear factor kappa B (NFκB). Moreover, assessment of tumour reduction was done by measuring tumour volume and percentage tumour reduction. A single dose of cisplatin (7.5 mg/kg) resulted in significant increase in serum creatinine, blood urea nitrogen, NF-kB, TNF-α and IL-6 levels along with decrease in albumin and IL-10 levels. However, there were no significant changes in raloxifene (8 mg/kg) treated group. Pre-treatment of raloxifene (8 mg/kg) caused marked decrease in serum creatinine, blood urea nitrogen, TNF-α and IL-6 levels whereas increase in albumin and IL-10 levels. However, pre-treatment of raloxifene showed maximum tumour reduction as compared to cisplatin and raloxifene treated groups. The present study demonstrates that raloxifene potentiates anti-tumour activity of cisplatin with simultaneous reduction in its nephrotoxicity, and this effect is attributed to its direct anti-inflammatory activity.
authors.affiliation: Laboratory of Molecular Pharmacology and Toxicology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gauhati Medical College, Guwahati, Assam, 781032, India. vinayak757@gmail.com.
authors.forename: Vinayak Sudhir
authors.identifier: http://orcid.org/0000-0002-1197-0446
authors.initials: VS
authors.lastname: Jamdade
authors.affiliation: Laboratory of Molecular Pharmacology and Toxicology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gauhati Medical College, Guwahati, Assam, 781032, India.
authors.forename: Nitin A
authors.initials: NA
authors.lastname: Mundhe
authors.affiliation: Laboratory of Molecular Pharmacology and Toxicology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gauhati Medical College, Guwahati, Assam, 781032, India.
authors.forename: Parveen
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Laboratory of Molecular Pharmacology and Toxicology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gauhati Medical College, Guwahati, Assam, 781032, India.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Tadla
authors.affiliation: Laboratory of Molecular Pharmacology and Toxicology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gauhati Medical College, Guwahati, Assam, 781032, India.|Laboratory of Pharmacology, Department of Pharmacology, Gauhati Medical College, Guwahati, Assam, 781032, India.
authors.forename: Mangala
authors.initials: M
authors.lastname: Lahkar
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D016328:NF-kappa B; D020849:Raloxifene Hydrochloride; D015127:9,10-Dimethyl-1,2-benzanthracene; D002945:Cisplatin
keywords: Cisplatin; Inflammation; Nephrotoxicity; Pro-inflammatory cytokines; Raloxifene