Journal
ANTI-CANCER DRUGS
Volume 22, Issue 10, Pages 978-985Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0b013e32834ac8fc
Keywords
drug discovery; GSK3 beta; ovarian cancer; Wnt; xenograft
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Funding
- Ovarian Cancer Research Fund [LT/UIC/01.2011]
- Center for Clinical and Translational Sciences
- NIH [1R01 MH072940-01]
- [R03 CA139492]
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Ovarian cancer is the most lethal gynecological malignancy among US women. Paclitaxel/carboplatin is the current drug therapy used to treat ovarian cancer, but most women develop drug resistance and recurrence of the disease, necessitating alternative strategies for treatment. A possible molecular target for cancer therapy is glycogen synthase kinase 3 beta (GSK3 beta), a downstream kinase in the Wnt signaling pathway that is overexpressed in serous ovarian cancer. Novel maleimide-based GSK3b inhibitors (GSK3 beta i) were synthesized, selected, and tested in vitro using SKOV3 and OVCA432 serous ovarian cancer cell lines. From a panel of 10 inhibitors, GSK3 beta i 9ING41 was found to be the most effective in vitro. 9ING41 induced apoptosis as indicated by 4',6-diamidino-2-phenylindole-positive nuclear condensation, poly (ADP-ribose) polymerase cleavage, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The mechanism for apoptosis was through caspase-3 cleavage. GSK3 beta i upregulated phosphorylation of the inhibitory serine residue of GSK3 beta in OVCA432 and SKOV3 cell lines and also inhibited phosphorylation of the downstream target glycogen synthase. An in-vivo xenograft study using SKOV3 cells demonstrated that tumor progression was hindered by 9ING41 in vivo. The maximum tolerated dose for 9ING41 was greater than 500 mg/kg in rats. Pharmacokinetic analysis showed 9ING41 to have a bioavailability of 4.5% and to be well distributed in tissues. Therefore, GSK3 beta inhibitors alone or in combination with existing drugs may hinder the growth of serous ovarian cancers. Anti-Cancer Drugs 22: 978-985 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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