Apoptotic and chemotherapeutic properties of iron(III)-salophene in an ovarian cancer animal model

Original Research

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Authors: Thilo S Lange, Carolyn McCourt, Rakesh K Singh, Kyu Kwang Kim, Ajay P Singh, et al

Published Date December 2008 Volume 2009:3 Pages 17 - 26

DOI: http://dx.doi.org/10.2147/DDDT.S4582

Thilo S Lange^1,2, Carolyn McCourt², Rakesh K Singh², Kyu Kwang Kim², Ajay P Singh³, Brian S Luisi⁴, Onur Alptürk⁵, Robert M Strongin⁶, Laurent Brard²

¹Division of Biology and Medicine Brown University, Providence, R1, USA; ²Molecular Therapeutics Laboratory, Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants’ Hospital of RI, Warren Alpert Medical School of Brown University, Providence, RI, USA; ³Department of Plant Biology, Rutgers University, New Brunswick, NJ, USA; ⁴Department of Chemistry, Brown University, Providence, RI, USA; ⁵Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; ⁶Department of Chemistry, Portland State University, Portland, OR, USA

Abstract: The cytotoxicity of organometallic compounds iron(III)-, cobalt(III)-, manganese(II)-, and copper(II)-salophene (-SP) on platinum-resistant ovarian cancer cell lines was compared. Fe-SP displayed selective cytotoxicity (IC₅₀ at ∼1 μM) against SKOV-3 and OVCAR-3 cell lines while Co-SP caused cytotoxic effects only at higher concentrations (IC₅₀ at 60 μM) and Cu-SP effects were negligible. High cytotoxicity of Mn-SP (30–60 μM) appeared to be nonspecific because the Mn-chloride salt reduced cell viability similarly. The effect of Fe-SP at 1 μM proved to be ovarian cancer cell selective when compared to a panel of cell lines derived from different tumors. The first irreversible step in the induction of cell death by Fe-SP occurred after 3 hrs as indicated by the mitochondrial transmembrane potential (ΔΨm) and was mainly linked to apoptotic, not necrotic events. To evaluate the toxicity of Fe-SP in vivo we conducted an acute toxicity study in rats. The LD₅₀ of Fe-SP is >2000 mg/kg orally and >5.5 mg/kg body weight by intraperitoneal injection. An ovarian cancer animal model showed that the chemotherapeutic relevant dose of Fe-SP in rats is 0.5–1 mg/kg body weight. The present report suggests that Fe-SP is a potential therapeutic drug to treat ovarian cancer.

Keywords: iron(III)-salophene, chemotherapeutic properties, p38 MAPK, ovarian cancer animal model

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