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

Enes Taylan; Fouzia Zayou; Ramachandran Murali; Beth Y Karlan; Stephen J Pandol; Mouad Edderkaoui; Sandra Orsulic

doi:10.1016/j.ygyno.2020.07.005

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

Gynecol Oncol. 2020 Oct;159(1):277-284. doi: 10.1016/j.ygyno.2020.07.005. Epub 2020 Jul 19.

Authors

Enes Taylan¹, Fouzia Zayou², Ramachandran Murali², Beth Y Karlan³, Stephen J Pandol⁴, Mouad Edderkaoui⁵, Sandra Orsulic⁶

Affiliations

¹ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
² Departments of Medicine, Biomedical Sciences, Radiation Oncology and Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Chemotherapy resistance; GSK3B; Glycogen synthase kinase 3 beta inhibitor; HDAC; Histone deacetylase inhibitor; Ovarian cancer.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cisplatin / pharmacology
Cisplatin / therapeutic use
Disease Models, Animal
Drug Resistance, Neoplasm / drug effects
Drug Screening Assays, Antitumor
Female
Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylase Inhibitors / therapeutic use
Humans
Mice
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / mortality
Ovarian Neoplasms / pathology
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding