Laurent Brard1, Cornelius O Granai, Narasimha Swamy. 1. Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI 02905, USA.
Abstract
OBJECTIVES: 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.
OBJECTIVES: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 humancancers 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 ratovarian 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.
Authors: Maida De Bortoli; Elena Taverna; Elisa Maffioli; Patrizia Casalini; Francesco Crisafi; Vikas Kumar; Claudio Caccia; Dario Polli; Gabriella Tedeschi; Italia Bongarzone Journal: J Exp Clin Cancer Res Date: 2018-04-03