Antiproliferative and apoptotic effects of iron chelators on human cervical carcinoma cells.
OBJECTIVE
Cervical carcinoma is a human papillomavirus (HPV)-associated cancer for which treatment options still mainly rely on surgical procedures, with or without adjuvant radiotherapy and chemotherapy. As iron may participate in the pathogenesis of viral infections and cancer in several ways, the present study was designed to investigate the effect of iron chelation on HPV-16- and HPV-18-positive cervical carcinoma cell lines.


METHODS
Desferrioxamine and deferiprone, two chemically unrelated iron chelators, were used to investigate the effect of iron chelation on SiHa and HeLa cells. Proliferation was investigated by cells counts, by [(3)H]thymidine uptake assay, and by immunostaining with Ki-67 and proliferating cell nuclear antigen (PCNA). Apoptosis was determined by morphological analysis, by a TUNEL assay, and by flow cytometry detecting FITC-conjugated annexin-V.


RESULTS
Desferrioxamine and deferiprone induced a time- and dose-dependent inhibition of SiHa and HeLa cell growth. The inhibition of cell growth was associated with a decrease in the expression of both stable and total PCNA and Ki-67, a proliferation marker whose expression may predict survival in uterine cervical carcinoma. TUNEL assay, flow cytometry with annexin-V-fluorescein, and morphological analysis indicated that iron chelation also induced a time- and dose-dependent apoptosis of both cell lines. This apoptotic effect was prevented by the addition of exogenous iron.


CONCLUSIONS
These results show that iron chelation inhibits the growth and induces the apoptosis of HPV-positive carcinoma cells. This suggests that iron chelators may represent a potential therapeutic approach for the management of cervical carcinoma.
Simonart
Thierry
T
Department of Dermatology, Erasme University Hospital, Brussels, B-1070, Belgium. tsimonar@ulb.ac.be
Boelaert
Johan R
JR
Mosselmans
Roger
R
Andrei
Graciela
G
Noel
Jean-Christophe
JC
De Clercq
Erik
E
Snoeck
Robert
R
D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D000077543:Deferiprone; D003676:Deferoxamine / Q000494:pharmacology*; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D027383:Papillomaviridae / Q000145:classification / Q000378:metabolism; D030361:Papillomavirus Infections / Q000150:complications / Q000378:metabolism / Q000821:virology; D011728:Pyridones / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000150:complications / Q000378:metabolism / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000821:virology
D006131:Growth Inhibitors; D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D003676:Deferoxamine