title: Tetrathiomolybdate sensitizes ovarian cancer cells to anticancer drugs doxorubicin, fenretinide, 5-fluorouracil and mitomycin C.
abstract: BACKGROUND
  Our recent study showed that tetrathiomolybdate (TM), a drug to treat copper overload disorders, can sensitize drug-resistant endometrial cancer cells to reactive oxygen species (ROS)-generating anticancer drug doxorubicin. To expand these findings in the present study we explore TM efficacy in combination with a spectrum of ROS-generating anticancer drugs including mitomycin C, fenretinide, 5-fluorouracil and doxorubicin in ovarian cancer cells as a model system.
  
  
  METHODS
  The effects of TM alone or in combination with doxorubicin, mitomycin C, fenretinide, or 5-fluorouracil were evaluated using a sulforhodamine B assay. Flow cytometry was used to detect the induction of apoptosis and ROS generation. Immunoblot analysis was carried out to investigate changes in signaling pathways.
  
  
  RESULTS
  TM potentiated doxorubicin-induced cytotoxicity and modulated key regulators of apoptosis (PARP, caspases, JNK and p38 MAPK) in SKOV-3 and A2780 ovarian cancer cell lines. These effects were linked to the increased production of ROS, as shown in SKOV-3 cells. ROS scavenging by ascorbic acid blocked the sensitization of cells by TM. TM also sensitized SKOV-3 to mitomycin C, fenretinide, and 5-fluorouracil. The increased cytotoxicity of these drugs in combination with TM was correlated with the activity of ROS, loss of a pro-survival factor (e.g. XIAP) and the appearance of a pro-apoptotic marker (e.g. PARP cleavage).
  
  
  CONCLUSIONS
  Our data show that TM increases the efficacy of various anticancer drugs in ovarian cancer cells in a ROS-dependent manner.
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. KKim@wihri.org
authors.forename: Kyu Kwang
authors.initials: KK
authors.lastname: Kim
authors.forename: Thilo S
authors.initials: TS
authors.lastname: Lange
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.forename: Laurent
authors.initials: L
authors.lastname: Brard
authors.forename: Richard G
authors.initials: RG
authors.lastname: Moore
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D017313:Fenretinide / Q000494:pharmacology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D008982:Molybdenum / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D017313:Fenretinide; D016685:Mitomycin; D004317:Doxorubicin; D008982:Molybdenum; C020809:tetrathiomolybdate; D005472:Fluorouracil