title: Assessment of the antitumor potential of Bithionol in vivo using a xenograft model of ovarian cancer.
abstract: In terms of the concept of 'drug repurposing', we focused on pharmaceutical-grade Bithionol (BT) as a therapeutic agent against ovarian cancer. Our recent in-vitro study provides preclinical data suggesting a potential therapeutic role for BT against recurrent ovarian cancer. BT was shown to cause cell death by caspases-mediated apoptosis. The present preliminary study further explores the antitumor potential of pharmaceutical-grade BT in an in-vivo xenograft model of human ovarian cancer. Nude Foxn1 mice bearing SKOV-3 human ovarian tumor xenografts were treated with titrated doses of BT and the therapeutic efficacy of pharmaceutical BT was determined using bioluminescence imaging. BT-induced changes in cell proliferation and apoptosis were evaluated by Ki-67 immunochemical staining and TUNEL assay. The effect of BT on autotaxin levels in serum, ascitic fluid, and tumor tissue was assessed by colorimetric and western blot techniques. BT treatment did not show antitumor potential or enhanced survival time at any of the doses tested. No apparent signs of toxicity were observed with any of the doses tested. Immunohistological analysis of tumor sections did not indicate a significant decrease in cellular proliferation (Ki-67 assay). An increase in apoptosis (by TUNEL assay) was observed in all BT-treated mice compared with vehicle-treated mice. Although BT did not show significant antitumor activity in the present study, the ability of BT to induce apoptosis still makes it a promising therapeutic agent. Further confirmatory and optimization studies are essential to enhance the therapeutic effects of BT.
authors.affiliation: aDepartment of Obstetrics and Gynecology, Division of Gynecology Oncology bLaboratory Animal Resource Center, Division of Laboratory Animal Medicine, Southern Illinois University School of Medicine, Springfield, Illinois, USA.
authors.forename: Vijayalakshmi N
authors.initials: VN
authors.lastname: Ayyagari
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Johnston
authors.forename: Laurent
authors.initials: L
authors.lastname: Brard
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001735:Bithionol / Q000009:adverse effects / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099189:Lysophospholipase D
chemical_list: D000970:Antineoplastic Agents; D001735:Bithionol; D051858:Forkhead Transcription Factors; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C090140:Whn protein