GSK-3 inhibitors enhance TRAIL-mediated apoptosis in human gastric adenocarcinoma cells

Wu, Yi; Hsieh, Chin Tung; Chiu, Ying Ming; Chou, Shen Chieh; Kao, Jung‐Ta; Shieh, Dong Chen; Lee, Yi Ju

doi:10.1371/journal.pone.0208094

Cited by 11 publications

(8 citation statements)

References 40 publications

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“…In this scenario, GSK-3 inhibitors were acting in a TP53-dependent fashion to induce sensitivity to TRAIL. Thus, GSK-3 was promoting resistance to TRAIL and acting as a tumor promoter [57].…”

Section: Combining Gsk-3 Inhibitors and Immunotherapymentioning

confidence: 99%

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Duda

Akula

Abrams

et al. 2020

Cells

184

132

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Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.

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Section: Combining Gsk-3 Inhibitors and Immunotherapymentioning

confidence: 99%

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Duda

Akula

Abrams

et al. 2020

Cells

184

132

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“…3-(4-Morpholinophenyl)acrylic Acid (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Prepared using the general procedure starting from 4-morpholinobenzaldehyde.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…5-Acryloyl-2,3-dihydro-2-([1,1′-biphenyl]-4-yl)-1,5-benzothiazepin-4(5H)-one (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Prepared using the general procedure starting from 2,3-dihydro-2-([1,1′-biphenyl]-4-yl)-1,5-benzothiazepin-4(5H)one (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Yield: 51%.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Discovery of Novel Benzothiazepinones as Irreversible Covalent Glycogen Synthase Kinase 3β Inhibitors for the Treatment of Acute Promyelocytic Leukemia

et al. 2021

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Recently, irreversible inhibitors have attracted great interest in antitumors due to their advantages of forming covalent bonds to target proteins. Herein, some benzothiazepinone compounds (BTZs) have been designed and synthesized as novel covalent GSK-3β inhibitors with high selectivity for the kinase panel. The irreversible covalent binding mode was identified by kinetics and mass spectrometry, and the main labeled residue was confirmed to be the unique Cys14 that exists only in GSK-3β. The candidate 4-3 (IC 50 = 6.6 μM) showed good proliferation inhibition and apoptosis-inducing ability to leukemia cell lines, low cytotoxicity on normal cell lines, and no hERG inhibition, which hinted the potential efficacy and safety. Furthermore, 4-3 exhibited decent pharmacokinetic properties in vivo and remarkably inhibited tumor growth in the acute promyelocytic leukemia (APL) mouse model. All the results suggest that these newly irreversible BTZ compounds might be useful in the treatment of cancer such as APL.

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“…These results indicate that these agents enhance TRAIL-induced apoptosis via multiple mechanisms in a cell type-specific manner. BIO-acetoxime is a selective inhibitor of GSK-3α/β, and its inhibition has been reported to enhance TRAIL-induced cell death [30][31][32][33][34]. CP-100356 is a P-glycoprotein inhibitor that was previously unknown as a TRAIL sensitizer.…”

Section: Discussionmentioning

confidence: 99%

Proscillaridin A Sensitizes Human Colon Cancer Cells to TRAIL-Induced Cell Death

Semba

Takamatsu

Komazawa-Sakon

et al. 2022

IJMS

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytotoxic cytokine that induces cancer cell death by binding to TRAIL receptors. Because of its selective cytotoxicity toward cancer cells, TRAIL therapeutics, such as recombinant TRAIL and agonistic antibodies targeting TRAIL receptors, have garnered attention as promising cancer treatment agents. However, many cancer cells acquire resistance to TRAIL-induced cell death. To overcome this issue, we searched for agents to sensitize cancer cells to TRAIL-induced cell death by screening a small-molecule chemical library consisting of diverse compounds. We identified a cardiac glycoside, proscillaridin A, as the most effective TRAIL sensitizer in colon cancer cells. Proscillaridin A synergistically enhanced TRAIL-induced cell death in TRAIL-sensitive and -resistant colon cancer cells. Additionally, proscillaridin A enhanced cell death in cells treated with TRAIL and TRAIL sensitizer, the second mitochondria-derived activator of caspase mimetic. Proscillaridin A upregulated TRAIL receptor expression, while downregulating the levels of the anti-cell death molecules, cellular FADD-like IL-1β converting enzyme-like inhibitor protein and Mcl1, in a cell type-dependent manner. Furthermore, proscillaridin A enhanced TRAIL-induced cell death partly via O-glycosylation. Taken together, our findings suggest that proscillaridin A is a promising agent that enhances the anti-cancer efficacy of TRAIL therapeutics.

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GSK-3 inhibitors enhance TRAIL-mediated apoptosis in human gastric adenocarcinoma cells

Cited by 11 publications

References 40 publications

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Discovery of Novel Benzothiazepinones as Irreversible Covalent Glycogen Synthase Kinase 3β Inhibitors for the Treatment of Acute Promyelocytic Leukemia

Proscillaridin A Sensitizes Human Colon Cancer Cells to TRAIL-Induced Cell Death

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