title: Sulforaphane, a natural constituent of broccoli, prevents cell death and inflammation in nephropathy.
abstract: Cisplatin (cis-diamminedichloroplatinum II, CIS) is a potent and widely used chemotherapeutic agent to treat various malignancies, but its therapeutic use is limited because of dose-dependent nephrotoxicity. Cell death and inflammation play a key role in the development and progression of CIS-induced nephropathy. Sulforaphane (SFN), a natural constituent of cruciferous vegetables such as broccoli, Brussels sprouts, etc., has been shown to exert various protective effects in models of tissue injury and cancer. In this study, we have investigated the role of prosurvival, cell death and inflammatory signaling pathways using a rodent model of CIS-induced nephropathy, and explored the effects of SFN on these processes. Cisplatin triggered marked activation of stress signaling pathways [p53, Jun N-terminal kinase (JNK), and p38-α mitogen-activated protein kinase (MAPK)] and promoted cell death in the kidneys (increased DNA fragmentation, caspases-3/7 activity, terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling), associated with attenuation of various prosurvival signaling pathways [e.g., extracellular signal-regulated kinase (ERK) and p38-β MAPK]. Cisplatin also markedly enhanced inflammation in the kidneys [promoted NF-κB activation, increased expression of adhesion molecules ICAM and VCAM, enhanced tumor necrosis factor-α (TNF-α) levels and inflammatory cell infiltration]. These effects were significantly attenuated by pretreatment of rodents with SFN. Thus, the cisplatin-induced nephropathy is associated with activation of various cell death and proinflammatory pathways (p53, JNK, p38-α, TNF-α and NF-κB) and impairments of key prosurvival signaling mechanisms (ERK and p38-β). SFN is able to prevent the CIS-induced renal injury by modulating these pathways, providing a novel approach for preventing this devastating complication of chemotherapy.
authors.affiliation: Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA.
authors.forename: Carlos Enrique
authors.initials: CE
authors.lastname: Guerrero-Beltrán
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Béla
authors.initials: B
authors.lastname: Horváth
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Rajesh
authors.forename: Edilia
authors.initials: E
authors.lastname: Tapia
authors.forename: Itzhel
authors.initials: I
authors.lastname: García-Torres
authors.forename: José
authors.initials: J
authors.lastname: Pedraza-Chaverri
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001937:Brassica / Q000737:chemistry*; D016923:Cell Death / Q000187:drug effects*; D002945:Cisplatin / Q000633:toxicity; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D017879:Isothiocyanates; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D048031:JNK Mitogen-Activated Protein Kinases; C016766:sulforaphane; D002945:Cisplatin