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

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

Enes Taylan  1 , Fouzia Zayou  2 , Ramachandran Murali  2 , Beth Y Karlan  3 , Stephen J Pandol  4 , Mouad Edderkaoui  5 , Sandra Orsulic  6
Affiliations

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

Enes Taylan et al. Gynecol Oncol. 2020 Oct.

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.

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Conflict of interest statement

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.

Figures

Fig. 1.
Fig. 1.
Chemical structures of newly-developed dual GSK3B and HDACs inhibitors.
Fig. 2.
Fig. 2.
The effects of dual GSK3B and HDACs inhibitor analogs on cancer cell survival compared to SAHA in three human (KURAMOCHI, OVCA420, OVSAHO) and one mouse (MOSE-HRas-Myc) ovarian cancer cell lines. * represents p < .05, and # represents p < .001 compared to control.
Fig. 3.
Fig. 3.
The effects of GSK3B (Tideglusib) and HDAC (SAHA) inhibitors alone and in combination on cancer cell survival compared to APCS-540 in two human (KURAMOCHI, OVSAHO) and two mouse (BR-Luc, ID8) ovarian cancer cell lines. * represents p < .05.
Fig. 4.
Fig. 4.
Cancer cell migration and invasion assay results. A) Representative Transwell migration and invasion assay images (100× magnification) from ID8 and BR-Luc cancer cells treated with different concentrations of APCS-540. Cancer cell migration and invasion abilities of both ID8 and BR-Luc cells were significantly reduced with 0.6 µM of APCS-540, and completely inhibited at 2.4 µM. B) Average number of migrated cancer cells treated with APCS-540 concentrations of 0.6 µM, 1.2 µM, and 2.4 µM compared to control in mouse (ID8, BR-Luc) and human (KURAMOCHI, OVSAHO) ovarian cancer cells. Average number of cells is given at log2 scale. * represents p < .05, and # represents p < .001 compared to control.
Fig. 5.
Fig. 5.
A) The effect of APCS-540 on cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) human ovarian cancer cells. B) APCS-540 (0.6 µM) decreased relative mRNA expression levels of cancer stemness markers in human (OVCA420) and mouse (BR-Luc) ovarian cancer cell lines cultured for 48 h. Relative mRNA expression level was determined based on the housekeeping gene mRNA expression level. * represents p < .05, and # represents p < .001 compared to control.
Fig. 6.
Fig. 6.
A) Baseline (pre-treatment) IVIS imaging results of mice i.p. injected with BR-Luc cells and assigned to the control (n = 9) and treatment (n = 9) groups. Imaging confirmed that all mice in both groups harbor intra-abdominal growing tumors. No statistically significant difference was observed at baseline between two groups. B) Survival assay results for mice treated with APCS-540 vs. control. Treatment with APCS-540 significantly increased survival in tumor-bearing mice by 66%.
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