Abstract C211: Therapeutic utility of GSK-3 inhibitors for the treatment of cancer
Authors: Chedid Marcio , Gutowski Magda , Evans Robert J. , Brail Leslie , Horton Noel D. , Jackson Kimberley , Engler Thomas A. 
Published: June 2012

Glycogen synthase kinase-3 (GSK-3) is a constitutively active protein kinase that plays a role in diverse signaling pathways. Initially described as a regulator of glycogen synthesis and metabolism, GSK-3 is now known to play a central role in a variety of cellular functions ranging from maintenance of stem cell function to regulation of cell cycle and apoptosis. In mammals, there are two highly homologous isoforms of GSK-3 (GSK-3α and GSK-3β) which share substrate specificity and functional properties. GSK3β is one of the key components of the β-catenin destruction complex and phosphorylation of β-catenin by GSK-3 targets the substrate protein for ubiquitylation and proteosomal destruction - conversely, inhibition of GSK-3β activity results in loss of phosphorylation sites and stabilization of β-catenin in the cellular cytoplasm and nucleus. GSK-3 expression and/or activity have been reported to be elevated in multiple tumor types, including pancreatic, gastric and colorectal carcinomas. Equally important, inhibition of GSK-3 expression in colorectal tumor cell lines via specific siRNAs induced apoptosis and attenuated the proliferation of tumor cells. Together, these findings suggest that GSK-3 inhibitors may represent a new class of therapeutic agents against colorectal cancer.

LY-GSK-3i is a novel, potent and selective ATP competitive inhibitor of both isoforms of GSK-3. In vitro, LY potently inhibits the enzymatic activity of GSK-3α and GSK-3β with IC50s of 1.5 nM and 0.9 nM, respectively. Pharmacologic activity of other GSK-3 inhibitors in the literature against cancer is not clear. LY-GSK-3i did not evidence useful antitumor activity in its own right against colorectal, ovarian or non-small cell lung (NSCL) tumor lines. However, when combined with different chemotherapeutic agents, LY was found to potentiate their pro-apoptotic activity. LY-GSK-3i was shown to significantly potentiate caspase-3 activation when combined cisplatin in HCT-116 and Colo-205 colorectal carcinoma lines. Enhancement of caspase-3 activity was also observed when LY-GSK-3i was combined with 5-fluorouracyl (5-FU) in HCT-116 cells. In order to explore the potential of LY-GSK-3i in other tumor types, we assessed the pro-apoptotic activity of the LY/cisplatin combination against ovarian (A2780) and lung (A549 and NCI-H460) cell lines. In all cases, LY-GSK-3i was shown to significantly elevate caspase-3 activity when compared to cisplatin alone. In vivo, administration of a single dose of LY-GSK-3i to xenograft-bearing mice lead to a time-and dose-dependent accumulation of the substrate protein -catenin in tumor tissues. In vivo xenograft growth studies revealed that administration of 5 mg/kg LY-GSK-3i in combination with cisplatin, given every 7 or 14 days, was sufficient to significantly improve the efficacy as compared to cisplatin alone given at the same intervals. Together, our findings provide evidence for the potential therapeutic utility of GSK-3 inhibitors for the treatment of cancer.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C211.