Entinostat Enhances the Efficacy of Chemotherapy in Small Cell Lung Cancer Through S-phase Arrest and Decreased Base Excision Repair.

Autor:	Solta A; Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Boettiger K; Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Kovács I; National Koranyi Institute of Pulmonology, Budapest, Hungary., Lang C; Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; Division of Pulmonology, Department of Medicine II, Medical University of Vienna, Austria., Megyesfalvi Z; Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; National Koranyi Institute of Pulmonology, Budapest, Hungary.; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary., Ferk F; Center for Cancer Research, Medical University Vienna, Vienna, Austria., Mišík M; Center for Cancer Research, Medical University Vienna, Vienna, Austria., Hoetzenecker K; Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Aigner C; Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Kowol CR; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria., Knasmueller S; Center for Cancer Research, Medical University Vienna, Vienna, Austria., Grusch M; Center for Cancer Research, Medical University Vienna, Vienna, Austria., Szeitz B; Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary., Rezeli M; Department of Biomedical Engineering, Lund University, Lund, Sweden., Dome B; Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; National Koranyi Institute of Pulmonology, Budapest, Hungary.; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary.; Department of Translational Medicine, Lund University, Lund, Sweden., Schelch K; Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; Center for Cancer Research, Medical University Vienna, Vienna, Austria.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Nov 14; Vol. 29 (22), pp. 4644-4659.
DOI:	10.1158/1078-0432.CCR-23-1795
Abstrakt:	Purpose: Acquired chemoresistance is a frequent event in small cell lung cancer (SCLC), one of the deadliest human malignancies. Histone deacetylase inhibitors (HDACi) have been shown to synergize with different chemotherapeutic agents including cisplatin. Accordingly, we aimed to investigate the dual targeting of HDAC inhibition and chemotherapy in SCLC. Experimental Design: The efficacy of HDACi and chemotherapy in SCLC was investigated both in vitro and in vivo. Synergistic drug interactions were calculated based on the HSA model (Combenefit software). Results from the proteomic analysis were confirmed via ICP-MS, cell-cycle analysis, and comet assays. Results: Single entinostat- or chemotherapy significantly reduced cell viability in human neuroendocrine SCLC cells. The combination of entinostat with either cisplatin, carboplatin, irinotecan, epirubicin, or etoposide led to strong synergy in a subset of resistant SCLC cells. Combination treatment with entinostat and cisplatin significantly decreased tumor growth in vivo. Proteomic analysis comparing the groups of SCLC cell lines with synergistic and additive response patterns indicated alterations in cell-cycle regulation and DNA damage repair. Cell-cycle analysis revealed that cells exhibiting synergistic drug responses displayed a shift from G1 to S-phase compared with cells showing additive features upon dual treatment. Comet assays demonstrated more DNA damage and decreased base excision repair in SCLC cells more responsive to combination therapy. Conclusions: In this study, we decipher the molecular processes behind synergistic interactions between chemotherapy and HDAC inhibition. Moreover, we report novel mechanisms to overcome drug resistance in SCLC, which may be relevant to increasing therapeutic success. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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