Identification of GSK3β Inhibitor Kenpaullone As a Temozolomide Enhancer Against Glioblastoma

Overview

Journal Sci Rep

Specialty Science

Date 2019 Jul 13

PMID 31296906

Citations 19

Authors

Tomohiro Kitabayashi

Yu Dong

Takuya Furuta

Hemragul Sabit

Shabierjiang Jiapaer

Jiakang Zhang

Guangtao Zhang

Yasuhiko Hayashi

Masahiko Kobayashi

Takahiro Domoto

Toshinari Minamoto

Atsushi Hirao

Mitsutoshi Nakada

Affiliations

Soon will be listed here.

Abstract

Cancer stem cells are associated with chemoresistance and rapid recurrence of malignant tumors, including glioblastoma (GBM). Although temozolomide (TMZ) is the most effective drug treatment for GBM, GBM cells acquire resistance and become refractory to TMZ during treatment. Therefore, glioma stem cell (GSC)-targeted therapy and TMZ-enhancing therapy may be effective approaches to improve GBM prognosis. Many drugs that suppress the signaling pathways that maintain GSC or enhance the effects of TMZ have been reported. However, there are no established therapies beyond TMZ treatment currently in use. In this study, we screened drug libraries composed of 1,301 existing drugs using cell viability assays to evaluate effects on GSCs, which led to selection of kenpaullone, a kinase inhibitor, as a TMZ enhancer targeting GSCs. Kenpaullone efficiently suppressed activity of glycogen synthase kinase (GSK) 3β. Combination therapy with kenpaullone and TMZ suppressed stem cell phenotype and viability of both GSCs and glioma cell lines. Combination therapy in mouse models significantly prolonged survival time compared with TMZ monotherapy. Taken together, kenpaullone is a promising drug for treatment of GBM by targeting GSCs and overcoming chemoresistance to TMZ.

Citing Articles

Urinary D-asparagine level is decreased by the presence of glioblastoma.

Nakade Y, Kinoshita M, Nakada M, Sabit H, Ichinose T, Mita M Acta Neuropathol Commun. 2024; 12(1):122.

PMID: 39164793 PMC: 11337596. DOI: 10.1186/s40478-024-01836-6.

Pharmacological Modulation of the Cytosolic Oscillator Affects Glioblastoma Cell Biology.

Wagner P, Fornasier S, Guido M Cell Mol Neurobiol. 2024; 44(1):51.

PMID: 38907776 PMC: 11193694. DOI: 10.1007/s10571-024-01485-2.

Glycogen synthase kinase 3β: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer.

Uehara M, Domoto T, Takenaka S, Takeuchi O, Shimasaki T, Miyashita T Cancer Drug Resist. 2024; 7:4.

PMID: 38318525 PMC: 10838383. DOI: 10.20517/cdr.2023.84.

Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets.

Watts M, Giadone R, Ordureau A, Holton K, Harper J, Rubin L Front Cell Neurosci. 2024; 17:1327361.

PMID: 38314348 PMC: 10834640. DOI: 10.3389/fncel.2023.1327361.

Transcriptomics analysis reveals distinct mechanism of breast cancer stem cells regulation in mammospheres from MCF-7 and T47D cells.

Hermawan A, Putri H, Fatimah N, Prasetio H Heliyon. 2024; 10(2):e24356.

PMID: 38304813 PMC: 10831612. DOI: 10.1016/j.heliyon.2024.e24356.

References

Bain J, McLauchlan H, Elliott M, Cohen P . The specificities of protein kinase inhibitors: an update. Biochem J. 2003; 371(Pt 1):199-204. PMC: 1223271. DOI: 10.1042/BJ20021535. View

Korur S, Huber R, Sivasankaran B, Petrich M, Morin Jr P, Hemmings B . GSK3beta regulates differentiation and growth arrest in glioblastoma. PLoS One. 2009; 4(10):e7443. PMC: 2757722. DOI: 10.1371/journal.pone.0007443. View

Wu C, Watts M, Rubin L . MAP4K4 Activation Mediates Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis. Cell Rep. 2019; 26(5):1143-1156.e5. DOI: 10.1016/j.celrep.2019.01.019. View

Du Z, Chen H, Liu H, Lu J, Qian K, Huang C . Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nat Commun. 2015; 6:6626. PMC: 4375778. DOI: 10.1038/ncomms7626. View

Codrici E, Enciu A, Popescu I, Mihai S, Tanase C . Glioma Stem Cells and Their Microenvironments: Providers of Challenging Therapeutic Targets. Stem Cells Int. 2016; 2016:5728438. PMC: 4764748. DOI: 10.1155/2016/5728438. View

Anido J, Saez-Borderias A, Gonzalez-Junca A, Rodon L, Folch G, Carmona M . TGF-β Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma. Cancer Cell. 2010; 18(6):655-68. DOI: 10.1016/j.ccr.2010.10.023. View

Meijer L, Flajolet M, Greengard P . Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci. 2004; 25(9):471-80. DOI: 10.1016/j.tips.2004.07.006. View

Marchand B, Tremblay I, Cagnol S, Boucher M . Inhibition of glycogen synthase kinase-3 activity triggers an apoptotic response in pancreatic cancer cells through JNK-dependent mechanisms. Carcinogenesis. 2011; 33(3):529-37. DOI: 10.1093/carcin/bgr309. View

Miyashita K, Kawakami K, Nakada M, Mai W, Shakoori A, Fujisawa H . Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma. Clin Cancer Res. 2009; 15(3):887-97. DOI: 10.1158/1078-0432.CCR-08-0760. View

10.

Hide T, Takezaki T, Nakamura H, Kuratsu J, Kondo T . Brain tumor stem cells as research and treatment targets. Brain Tumor Pathol. 2008; 25(2):67-72. DOI: 10.1007/s10014-008-0237-5. View

11.

Reinhardt L, Kordes S, Reinhardt P, Glatza M, Baumann M, Drexler H . Dual Inhibition of GSK3β and CDK5 Protects the Cytoskeleton of Neurons from Neuroinflammatory-Mediated Degeneration In Vitro and In Vivo. Stem Cell Reports. 2019; 12(3):502-517. PMC: 6409486. DOI: 10.1016/j.stemcr.2019.01.015. View

12.

Pyko I, Nakada M, Sabit H, Teng L, Furuyama N, Hayashi Y . Glycogen synthase kinase 3β inhibition sensitizes human glioblastoma cells to temozolomide by affecting O6-methylguanine DNA methyltransferase promoter methylation via c-Myc signaling. Carcinogenesis. 2013; 34(10):2206-17. DOI: 10.1093/carcin/bgt182. View

13.

Liu M, Zang T, Zhang C . Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients. Cell Rep. 2016; 14(1):115-128. PMC: 4706770. DOI: 10.1016/j.celrep.2015.12.018. View

14.

Tien Y, Chang M, Chu P, Lin C, Liu C, Liao A . Downregulation of the KLF4 transcription factor inhibits the proliferation and migration of canine mammary tumor cells. Vet J. 2015; 205(2):244-53. DOI: 10.1016/j.tvjl.2014.12.031. View

15.

Rhim J, Luo X, Xu X, Gao D, Zhou T, Li F . A High-content screen identifies compounds promoting the neuronal differentiation and the midbrain dopamine neuron specification of human neural progenitor cells. Sci Rep. 2015; 5:16237. PMC: 4635364. DOI: 10.1038/srep16237. View

16.

Reyderman L, Statkevich P, Thonoor C, Patrick J, Batra V, Wirth M . Disposition and pharmacokinetics of temozolomide in rat. Xenobiotica. 2004; 34(5):487-500. DOI: 10.1080/00498250410001685737. View

17.

Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G . Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006; 13(7):1238-41. DOI: 10.1038/sj.cdd.4401872. View

18.

Leost M, Schultz C, Link A, Wu Y, Biernat J, Mandelkow E . Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Eur J Biochem. 2000; 267(19):5983-94. DOI: 10.1046/j.1432-1327.2000.01673.x. View

19.

Chowdhary S, Ryken T, Newton H . Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: a meta-analysis. J Neurooncol. 2015; 122(2):367-82. PMC: 4368843. DOI: 10.1007/s11060-015-1724-2. View

20.

Nakada M, Niska J, Miyamori H, McDonough W, Wu J, Sato H . The phosphorylation of EphB2 receptor regulates migration and invasion of human glioma cells. Cancer Res. 2004; 64(9):3179-85. DOI: 10.1158/0008-5472.can-03-3667. View