title: Spongean alkaloids protect rat kidney cells against cisplatin-induced cytotoxicity.
abstract: Nephrotoxicity is the major dose-limiting adverse effect of cisplatin (CisPt) and results from CisPt-induced damage of tubular cells. Nephroprotective strategies are preferential to improve supportive care in cancer. We investigated a subset of purified substances originating from various plants or from marine sponges as to their potency to protect rat renal tubular cells (NRK-52E) against the cytotoxic and genotoxic effects of cisplatin. Cotreatment with a substance pool containing five purified substances originating from marine sponges increased the viability of NRK-52E cells following cisplatin treatment. Cytoprotection was accompanied by a reduced level of DNA damage as indicated by a lower amount of S139 phosphorylated histone H2AX (γH2AX) 24 h after treatment. Cytoprotection and genoprotection by the sponge substance pool did not comprise the anthracycline derivative doxorubicin. The spongean alkaloid aaptamine was identified as major bioactive compound that mediates cisplatin resistance. Aeroplysinin-1 was less cytoprotective than aaptamine. Notably, aaptamine preferentially conferred resistance to cisplatin, but not to oxaliplatin. Cytoprotection by aaptamine was also observed in rat glomerular endothelial cells, but not in RT-112 bladder cancer cells. Protection by aaptamine does not rest on a reduced formation of DNA damage caused by cisplatin treatment. Aaptamine and aeroplysinin-1 affected cisplatin-stimulated DDR as reflected on the level of S15-phosphorlyated p53 and S345-phosphorylated checkpoint kinase-1. Summarizing, the spongean alkaloid aaptamine alleviates cisplatin-induced damage in tubular and glomerular rat kidney cells. Therefore, we hypothesize that aaptamine might be useful to widen the therapeutic window of a cisplatin-based therapeutic regimen.
authors.affiliation: aInstitute of Toxicology, Heinrich Heine University, Moorenstrasse 5, Düsseldorf bInstitute of Pharmaceutical Biology and Biotechnology, Universitätsstrasse 1, Düsseldorf cInstitute for Cell Biology, University Duisburg-Essen, Hufeland Strasse 55, Essen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Funk
authors.forename: Katharina
authors.initials: K
authors.lastname: Krüger
authors.forename: Christian
authors.initials: C
authors.lastname: Henninger
authors.forename: Wim
authors.initials: W
authors.lastname: Wätjen
authors.forename: Peter
authors.initials: P
authors.lastname: Proksch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Thomale
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritz
mesh_terms: D000097:Acetonitriles / Q000494:pharmacology; D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D053138:Cyclohexenes / Q000494:pharmacology; D019610:Cytoprotection; D004249:DNA Damage; D004347:Drug Interactions; D006657:Histones / Q000378:metabolism; D006801:Humans; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D007680:Kidney Neoplasms; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D009287:Naphthyridines / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology; D050199:Podocytes / Q000187:drug effects; D011161:Porifera / Q000737:chemistry*; D051381:Rats
chemical_list: D000097:Acetonitriles; D000470:Alkaloids; D000970:Antineoplastic Agents; D053138:Cyclohexenes; C468783:H2AX protein, human; D006657:Histones; D009287:Naphthyridines; D009944:Organoplatinum Compounds; D010936:Plant Extracts; D000077150:Oxaliplatin; C042151:aeroplysinin I; C043986:aaptamine; D002945:Cisplatin