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

Abstract

Purpose: Acquired chemoresistance is a frequent event in small resistant SCLC cells. Combination treatment with entinostat and cell lung cancer (SCLC), one of the deadliest human malignancies. cisplatin significantly decreased tumor growth in vivo. Proteomic Histone deacetylase inhibitors (HDACi) have been shown to analysis comparing the groups of SCLC cell lines with synergistic synergize with different chemotherapeutic agents including cisplat- and additive response patterns indicated alterations in cell-cycle in. Accordingly, we aimed to investigate the dual targeting of HDAC regulation and DNA damage repair. Cell-cycle analysis revealed inhibition and chemotherapy in SCLC. that cells exhibiting synergistic drug responses displayed a shift Experimental Design: The efficacy of HDACi and chemotherfrom G1 to S-phase compared with cells showing additive features apy in SCLC was investigated both in vitro and in vivo. Synergistic upon dual treatment. Comet assays demonstrated more DNA drug interactions were calculated based on the HSA model (Com-damage and decreased base excision repair in SCLC cells more benefit software). Results from the proteomic analysis were con-responsive to combination therapy. firmed via ICP-MS, cell-cycle analysis, and comet assays. Conclusions: In this study, we decipher the molecular processes Results: Single entinostat- or chemotherapy significantly behind synergistic interactions between chemotherapy and HDAC reduced cell viability in human neuroendocrine SCLC cells. The inhibition. Moreover, we report novel mechanisms to overcome combination of entinostat with either cisplatin, carboplatin, irinodrug resistance in SCLC, which may be relevant to increasing tecan, epirubicin, or etoposide led to strong synergy in a subset of therapeutic success.