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Open Access Highly Accessed Research article

Tetrathiomolybdate sensitizes ovarian cancer cells to anticancer drugs doxorubicin, fenretinide, 5-fluorouracil and mitomycin C

Kyu Kwang Kim1*, Thilo S Lange12, Rakesh K Singh1, Laurent Brard3 and Richard G Moore1

Author Affiliations

1 Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School, Brown University, 101 Dudley Street, Providence, RI 02905, USA

2 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA

3 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA

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BMC Cancer 2012, 12:147  doi:10.1186/1471-2407-12-147

Published: 13 April 2012

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.

Keywords:
Tetrathiomolybdate; Combination treatment; Doxorubicin; Mitomycin C; Fenretinide; 5-fluorouracil; ROS generation