Iron chelators deferoxamine and diethylenetriamine pentaacetic acid induce apoptosis in ovarian carcinoma.
OBJECTIVE
Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Deprivation of iron (Fe), an essential micro-nutrient, by chelation is known to inhibit proliferation of several human cancers but its potential in ovarian cancer treatment remains unknown. We have evaluated the anti-proliferative activities of iron chelators, deferoxamine (DFO), and diethylenetriamine pentaacetic acid (DTPA), in human and rat ovarian cancer cells.


METHODS
The effect of DFO and DTPA on CaOV-3 (human) and NUTU-19 (rat) ovarian cancer cells was determined by cell proliferation and apoptosis assays (Hoechst staining, DNA fragmentation, and caspase activation), cell cycle analysis, and Fe supplementation studies.


RESULTS
DFO and DTPA were cytotoxic to ovarian cancer cells in a dose- and time-dependent manner. DFO inhibited proliferation of NUTU-19 and CaOV-3 cells (IC(50) at 45 and 280 microM, respectively), while DTPA inhibited proliferation of only NUTU-19 cells (IC(50) at 50 microM), at 48 h. DNA synthesis was inhibited in CaOV-3 cells by DFO (>90% at 200 microM) and in NUTU-19 by both DFO and DTPA (>90% at 50 microM). Fe supplementation effectively reversed the cytotoxic effects of DFO and DTPA. Cell cycle analysis showed a G0/G1- and S-phase block with increased apoptosis. DNA fragmentation analysis confirmed apoptosis. Increase in caspase-3, -8, and -9 activities ( approximately 2.4-fold) was associated with apoptosis.


CONCLUSIONS
Our studies show that Fe chelators suppress ovarian cancer growth by inhibiting proliferation and inducing apoptosis. Therefore, Fe chelators can be potentially developed as novel therapeutic agents to treat ovarian cancer.
Brard
Laurent
L
Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI 02905, USA.
Granai
Cornelius O
CO
Swamy
Narasimha
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology*; D004789:Enzyme Activation; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D004369:Pentetic Acid / Q000494:pharmacology*; D051381:Rats
D006131:Growth Inhibitors; D007502:Iron Chelating Agents; D004369:Pentetic Acid; D007501:Iron; D020169:Caspases; D003676:Deferoxamine