Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@jax.org
Ref Type | Journal Article | ||||||||||||
PMID | (21878813) | ||||||||||||
Authors | Hilliard TS, Gaisina IN, Muehlbauer AG, Gaisin AM, Gallier F, Burdette JE | ||||||||||||
Title | Glycogen synthase kinase 3β inhibitors induce apoptosis in ovarian cancer cells and inhibit in-vivo tumor growth. | ||||||||||||
|
|||||||||||||
URL | |||||||||||||
Abstract Text | 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 3β (GSK3β), a downstream kinase in the Wnt signaling pathway that is overexpressed in serous ovarian cancer. Novel maleimide-based GSK3β inhibitors (GSK3βi) were synthesized, selected, and tested in vitro using SKOV3 and OVCA432 serous ovarian cancer cell lines. From a panel of 10 inhibitors, GSK3βi 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. GSK3βi upregulated phosphorylation of the inhibitory serine residue of GSK3β 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, GSK3β inhibitors alone or in combination with existing drugs may hinder the growth of serous ovarian cancers. |
Molecular Profile | Treatment Approach |
---|
Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
---|
Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
---|
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
---|
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
---|
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|