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Abstract
BackgroundConcurrent thoracic radiation plus chemotherapy is the mainstay of first-line treatment for limited-stage small cell lung cancer (LS-SCLC). Despite initial high responsiveness to combined chemo- and radiotherapy, SCLC almost invariably relapses and develops resistance within one year, leading to poor prognosis in patients with LS-SCLC. Developing new chemical agents that increase ionizing radiation’s cytotoxicity against SCLC is urgently needed.ResultsDual histone deacetylase (HDAC) and PI3K inhibitor FK228 not only displayed potent anticancer activity, but also enhanced the therapeutic effects of radiotherapy in SCLC cells. Mechanistically, radioresistant SCLC cells exhibit a lower level of histone H3K9 acetylation and a higher expression level of the MRE11-RAD50-NBS1 (MRN) complex and show more efficient and redundant DNA damage repair capacities than radiosensitive SCLC cells. FK228 pretreatment resulted in marked induction of H3k9 acetylation, attenuated homologous recombination (HR) repair competency and impaired non-homologous end joining (NHEJ) repair efficacy, leading to the accumulation of radiation-induced DNA damage and radiosensitization.ConclusionThe study uncovered that FK228 sensitized human radioresistant SCLC cells to radiation mainly through induction of chromatin decondensation and suppression of DNA damage signaling and repair. Our study provides a rational basis for a further clinical study to test the potential of FK228 as a radiosensitizing agent to increase the radiation-induced tumor cell kill in LS-SCLC patients.
Highlights
Small cell lung cancer (SCLC) is poorly differentiated and high-grade neuroendocrine carcinoma representing about 15–20% of all lung cancer cases [1, 2]
We found that FK228 inhibited the growth of SCLC cells by inducing apoptosis in vitro
FK228 inhibited the PI3K signaling pathway and exerted strong cytotoxic effects on SCLC cells Previous studies have shown that the PI3K signaling pathway is frequently active in SCLC cells [22], and suppression of the PI3K pathway by histone deacetylase inhibitor (HDACi) is cell type-specific
Summary
Small cell lung cancer (SCLC) is poorly differentiated and high-grade neuroendocrine carcinoma representing about 15–20% of all lung cancer cases [1, 2]. Despite the high responsiveness to concurrent chest radiation plus chemotherapy, LS-SCLC commonly relapses within. Radiation therapy induces various types of DNA damage, such as base damage, single-strand breaks (SSBs) or double-strand breaks (DSBs), and cross-linking of DNA– DNA. Such DNA insults, if left unrepaired, could eventually result in cell death. Concurrent thoracic radiation plus chemotherapy is the mainstay of first-line treatment for limitedstage small cell lung cancer (LS-SCLC). Despite initial high responsiveness to combined chemo- and radiotherapy, SCLC almost invariably relapses and develops resistance within one year, leading to poor prognosis in patients with LS-SCLC. Developing new chemical agents that increase ionizing radiation’s cytotoxicity against SCLC is urgently needed
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