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One important aspect about GSK inhibitors is their effect
One important aspect about GSK-3 inhibitors is their effect on pluripotency of Dexamethasone [4]. Many GSK-3 inhibitors are ATP-competitive and suppress both GSK-3alpha and GSK-3beta [476]. BIO was shown to suppress GSK-3 activity and promote Wnt/beta-catenin signaling. This combination of events preserved the pluripotency of human and mouse embryonic stem cells (ESCs) [477]. However, prolonged inhibition or activation of GSK-3 and Wnt signaling respectively resulted in differentiation of ESCs into multipotent mesendodermal progenitors or their differentiated progenitors [478], [479], [480]. The Hh, Notch and Wnt pathways can regulate cell fate determination and maintenance of stem cells. All of these pathways are regulated by GSK-3. GLI2 is a part of the Hh pathway that can be phosphorylated by GSK-3 [481]. Suppression of GSK-3 activity by BIO in canine melanoma cells enhanced beta-catenin activity and reduced migration and proliferation [482].
Various diseases including: neurological, diabetes, obesity, ischemia, sepsis, colitis and cancer have been postulated to be targets for GSK-3 inhibitors. However, caution has been suggested before treatment of cancers with GSK-3 inhibitors as GSK-3 can phosphorylate such pro-oncogenic factors as beta-catenin, c-Jun and c-Myc that target them for degradation [476]. However, as stated above, in certain circumstances, enhanced beta-catenin activity observed after GSK-3 inhibitor treatment was associated with reduced migration and proliferation. Indeed, suppressed proliferation was observed after either GSK-3 inhibitor treatment or GSK-3 knock-down in many cancers examined, including: brain, CRC, hematopoietic, melanoma, ovarian, pancreatic, paraganglioma, pheochromocytoma, prostate and thyroid cancers [483]. Patients with bi-polar disorder have been treated with the GSK-3 inhibitor lithium for decades and there does not appear to be any evidence of increased cancer incidence in these patients [484].
It is also possible to increase the effects of GSK-3 inhibitors by combining them with inhibitors that target key components of other signaling pathways. Combining the GSK-3 inhibitor AR-A014418 with the PKC-beta inhibitor enzastaurin was shown to have enhanced cytotoxicity against cutaneous T-cell lymphomas (CTCL). This combined treatment resulted in increased beta-catenin protein and transcriptional activity and decreased the level of CD44 [485]. Not surprisingly, a common aspect of many GSK-3 inhibitors is that they increase beta-catenin protein levels and transcriptional activity which is also necessary for their cytotoxic effects of the GSK-3 inhibitors.
Brief overview of Wnt/beta-catenin inhibitors
It is not surprising that Wnt-beta-catenin has been a key therapeutic target for over 20years due to the observations that elevated Wnt/beta-catenin signaling is detected in colorectal and other cancers. This has resulted in the discovery of inhibitors that can suppress this pathway [486], [487], [488], [489], [490], [491]. Recently an Achilles' heel has been observed in beta-catenin, its activity is iron-dependent. This iron-dependency has been exploited in the discovery and characterization of beta-catenin inhibitors that suppress beta-catenin stabilization due to their iron chelation abilities. Some of the inhibitors have been examined in clinical trials [492], [493], [494]. In certain cancers, if iron is elevated so is Wnt/beta-catenin signaling. This can result in enhanced tumorigenesis [494].
Another approach to suppress Wnt/beta-catenin is with common drugs such as non-steroidal anti-inflammatory drug (NSAIDs) and celecoxib. Aspirin, ibuprofen and naproxen are common NSAIDS which inhibit both COX1 and COX2, while celocoxib inhibits COX2. These drugs have been shown to inhibit beta-catenin-dependent transcription in CRCs and other cell types [495], [496]. Moreover the more specific COX2-inhibitor celecoxib can reduce polyp formation in patients with FAP [497], [498].