Dual targeting of GSK3B and HDACs reduces tumor growth and improves survival in an ovarian cancer mouse model.

Animals Antineoplastic Agents / pharmacology Apoptosis / drug effects Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Cisplatin / pharmacology Disease Models, Animal Drug Resistance, Neoplasm / drug effects Drug Screening Assays, Antitumor Female Glycogen Synthase Kinase 3 beta / antagonists & inhibitors Histone Deacetylase Inhibitors / pharmacology Humans Mice Ovarian Neoplasms / drug therapy Protein Kinase Inhibitors / pharmacology
Chemotherapy resistance GSK3B Glycogen synthase kinase 3 beta inhibitor HDAC Histone deacetylase inhibitor Ovarian cancer

Journal

Gynecologic oncology
ISSN: 1095-6859
Titre abrégé: Gynecol Oncol
Pays: United States
ID NLM: 0365304

Informations de publication

Date de publication:
10 2020
Historique:
received: 15 05 2020
accepted: 04 07 2020
pubmed: 24 7 2020
medline: 15 4 2021
entrez: 24 7 2020
Statut: ppublish

Résumé

To investigate the anti-tumor effect of a newly-developed dual inhibitor (APCS-540) of glycogen synthase kinase 3 beta (GSK3B) and histone deacetylases (HDACs) in ovarian cancer cells. The effects of APCS-540 on cancer cell proliferation, migration, invasion and cancer stemness were investigated in vitro in human (KURAMOCHI, OVCA420, OVSAHO) and mouse (BR-Luc, ID8, MOSE-HRas-Myc) ovarian cancer cells. Cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) cell lines were used to evaluate APCS-540's effect on chemoresistance. The immunocompetent syngeneic mouse model BR-Luc was used to test the effect of APCS-540 on ovarian cancer progression and survival. APCS-540 showed significant anti-tumor effects in vitro in both human and mouse ovarian cancer cells. Importantly, APCS-540 demonstrated marked cytotoxicity against cisplatin-resistant cancer cells and reversed cisplatin-resistance when used in combination with platinum. APCS-540 significantly decreased cancer cell invasion. A significant 66% increase in survival was observed in mice treated with APCS-540 compared to control mice. Dual inhibition of GSK3B and HDACs via APCS-540 showed potent anti-tumor activity in vitro and in vivo, suggesting that APCS-540 may provide a novel treatment option for ovarian cancer, including the platinum-resistant disease.

Identifiants

DOI: 10.1016/j.ygyno.2020.07.005 PMID: 32698955 PMC: PMC7769125
pubmed: 32698955
pii: S0090-8258(20)32380-5
doi: 10.1016/j.ygyno.2020.07.005
pmc: PMC7769125
mid: NIHMS1611620
pii:
doi:

Substances chimiques

Antineoplastic Agents 0
Histone Deacetylase Inhibitors 0
Protein Kinase Inhibitors 0
GSK3B protein, human EC 2.7.11.1
Glycogen Synthase Kinase 3 beta EC 2.7.11.1
Gsk3b protein, mouse EC 2.7.11.1
Cisplatin Q20Q21Q62J

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

277-284

Subventions

Organisme : NCI NIH HHS
ID : P01 CA233452
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA208753
Pays : United States
Organisme : NCI NIH HHS
ID : R41 CA235842
Pays : United States

Informations de copyright

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest M.E., R.M., and S.J.P. are co-inventors in the patent related to APCS-540 and they disclose their relationship with Avenzoar Pharmaceuticals (U.S. patent No. 10,029,997 B2 and U.S. patent No. 10,266,505 B2). S.O. and B.Y.K. have patents on gene signatures in ovarian cancer that could potentially be used to triage patients for targeted therapies (US010253368 and EU2908913). The remaining authors have no potential conflict of interest to declare.

Références

Cell Death Dis. 2015 Feb 19;6:e1657
pubmed: 25695609
Nat Rev Clin Oncol. 2020 Feb;17(2):91-107
pubmed: 31570827
Oncotarget. 2016 May 10;7(19):27538-51
pubmed: 27050373
Gastroenterology. 2018 Dec;155(6):1985-1998.e5
pubmed: 30144430
Sci Rep. 2017 Dec 4;7(1):16827
pubmed: 29203787
Nat Rev Dis Primers. 2016 Aug 25;2:16061
pubmed: 27558151
J Hematol Oncol. 2010 Feb 04;3:5
pubmed: 20132536
Sci Rep. 2018 Aug 17;8(1):12394
pubmed: 30120290
J Mol Signal. 2010 Jul 16;5:9
pubmed: 20637111
Gut. 2012 Mar;61(3):439-48
pubmed: 22147512
Curr Pharm Des. 2014;20(11):1847-56
pubmed: 23888962
Anticancer Drugs. 2011 Nov;22(10):978-85
pubmed: 21878813
Elife. 2019 May 03;8:
pubmed: 31050342
NPJ Precis Oncol. 2018 Sep 17;2:20
pubmed: 30246154
Cell. 2012 Jul 6;150(1):12-27
pubmed: 22770212
Cell Metab. 2016 Jan 12;23(1):27-47
pubmed: 26771115
Nat Rev Drug Discov. 2004 Jun;3(6):479-87
pubmed: 15173837
Clin Cancer Res. 2017 Apr 15;23(8):1891-1897
pubmed: 28053024
Oncotarget. 2016 Jan 26;7(4):4167-82
pubmed: 26716409
Oncogene. 2001 Aug 9;20(35):4768-76
pubmed: 11521189
Sci Rep. 2015 Nov 12;5:16555
pubmed: 26560046
Nat Rev Cancer. 2013 Oct;13(10):714-26
pubmed: 24060863
Oncogene. 2011 Aug 25;30(34):3705-15
pubmed: 21441955
Cancer Cell. 2018 May 14;33(5):801-815
pubmed: 29763622
J Clin Oncol. 2015 Dec 1;33(34):4015-22
pubmed: 26351349
Cancer Cell. 2002 Feb;1(1):53-62
pubmed: 12086888

Auteurs

Enes Taylan (E)

Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Fouzia Zayou (F)

Departments of Medicine, Biomedical Sciences, Radiation Oncology and Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Ramachandran Murali (R)

Departments of Medicine, Biomedical Sciences, Radiation Oncology and Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Beth Y Karlan (BY)

Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.

Stephen J Pandol (SJ)

Departments of Medicine, Biomedical Sciences, Radiation Oncology and Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Mouad Edderkaoui (M)

Departments of Medicine, Biomedical Sciences, Radiation Oncology and Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: Mouad.Edderkaoui@cshs.org.

Sandra Orsulic (S)

Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: SOrsulic@mednet.ucla.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Survie cellulaire › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Produits chimiques inorganiques › Composés du platine › Cisplatine › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de criblage d'agents antitumoraux › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Proline-directed protein kinases › Glycogen Synthase Kinase 3 › Glycogen synthase kinase 3 beta › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de désacétylase d'histone › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Maladies endocriniennes › Troubles gonadiques › Maladies ovariennes › Tumeurs de l'ovaire › Dual targeting of GSK3B and HDACs reduces...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Dual targeting of GSK3B and HDACs reduces...