title: Cytotoxic properties of Adamantyl isothiocyanate and potential in vivo metabolite adamantyl-N-acetylcystein in gynecological cancer cells.
abstract: This study determined the in vitro potential of novel compounds adamantyl-N-acetylcystein and adamantyl isothiocyanate to treat gynecological cancers. Adamantyl-N-acetylcystein is postulated to be an in vivo metabolite of adamantyl isothiocyanate as dietary isothiocyanates are converted to N-acetylcysteine-conjugates. A viability assay suggested that adamantyl isothiocyanate and adamantyl-N-acetylcystein are cytotoxic to cancer cells including gynecological cell lines. A NCI60 cancer cell assay revealed that growth-inhibition and cytotoxicity of adamantyl-N-acetylcystein were cell line, but not tissue type-specific. Cell cycle studies revealed that adamantyl-N-acetylcystein and adamantyl isothiocyanate arrest SKOV-3 ovarian cancer cells in G2/M phase. By TUNEL, immunoblotting, and viability studies employing caspase and p38 mitogen-activated protein kinase inhibitors, we proved that reduction in SKOV-3 viability is a consequence of DNA fragmentation and apoptosis. Cytotoxic action of adamantyl-N-acetylcystein in SKOV-3 and endometrial cancer (ECC-1, RL95-2, AN3CA, and KLE) cells required excess generation of reactive oxygen species which could be blocked by antioxidant co-treatment. Adamantyl-N-acetylcystein treatment led to modified expression or activation of apoptotic and oncogenic proteins such as JNK/SAPK, AKT, XIAP, and EGF-R for SKOV-3 and JNK/SAPK and ERK1/2 for ECC-1 cells. We suggest the further development of adamantyl-N-acetylcystein by sensitizing cells to the drug using signaling inhibitors or redox-modulating agents and by evaluating the drug efficacy in ovarian and endometrial in-vivo tumor models.
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School, Brown University, Providence, RI 02905, USA. thilo_lange@brown.edu
authors.forename: Thilo S
authors.initials: TS
authors.lastname: Lange
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Horan
authors.forename: Kyu K
authors.initials: KK
authors.lastname: Kim
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Singh
authors.forename: Nicholi
authors.initials: N
authors.lastname: Vorsa
authors.forename: Laurent
authors.initials: L
authors.lastname: Brard
authors.forename: Richard G
authors.initials: RG
authors.lastname: Moore
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D017879:Isothiocyanates / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010051:Ovarian Neoplasms; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C571392:adamantyl isothiocyanate; C571393:adamantyl-N-acetylcystein; C037152:isothiocyanic acid; D020928:Mitogen-Activated Protein Kinases; D000218:Adamantane; D000111:Acetylcysteine