Enes Taylan1, Fouzia Zayou2, Ramachandran Murali2, Beth Y Karlan3, Stephen J Pandol4, Mouad Edderkaoui5, Sandra Orsulic6. 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.
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.
Authors: Ali Aghdassi; Matthias Sendler; Annett Guenther; Julia Mayerle; Claas-Olsen Behn; Claus-Dieter Heidecke; Helmut Friess; Markus Büchler; Matthias Evert; Markus M Lerch; Frank Ulrich Weiss Journal: Gut Date: 2011-12-05 Impact factor: 23.059
Authors: I Rettig; E Koeneke; F Trippel; W C Mueller; J Burhenne; A Kopp-Schneider; J Fabian; A Schober; U Fernekorn; A von Deimling; H E Deubzer; T Milde; O Witt; I Oehme Journal: Cell Death Dis Date: 2015-02-19 Impact factor: 8.469
Authors: Katharina Dötzer; Friederike Schlüter; Franz Edler von Koch; Christine E Brambs; Sabine Anthuber; Sergio Frangini; Bastian Czogalla; Alexander Burges; Jens Werner; Sven Mahner; Barbara Mayer Journal: Biomedicines Date: 2021-03-12