小细胞肺癌（SCLC）迫切需要新的治疗方法。我们发现抗生素衍生化合物异戊酰螺旋霉素 I (ISP-I) 在体外和体内均对 SCLC 细胞系 H1048 和 DMS53 具有有效的抗肿瘤活性。 ISP-I 在两种细胞系中诱导细胞凋亡、G2/M 期细胞周期停滞和线粒体呼吸链功能障碍。综合RNA测序显示，ISP-I的抗SCLC作用主要归因于ATR/CHK1介导的DNA损伤反应和PERK/eIF2α/ATF4/CHOP介导的ER应激。重要的是，活性氧 (ROS) 清除剂 N-乙酰基-L-半胱氨酸 (NAC) 减轻了 ISP-I 诱导的 DNA 损伤、内质网应激和细胞凋亡，这强调了 ROS 在抗 SCLC 中的关键作用ISP-I 机制。此外，ISP-I 治疗诱导 SCLC 细胞中的免疫原性细胞死亡 (ICD)，三磷酸腺苷 (ATP) 分泌增加、高迁移率族蛋白 1 (HMGB1) 释放增加以及钙网蛋白 (CRT) 暴露增加证明了这一点。细胞表面。此外，网络药理学分析结合细胞热位移测定（CETSA）和放线菌酮（CHX）追踪实验，证明ISP-I作为脱嘌呤/脱嘧啶核酸内切酶1（APEX1）的配体并促进其降解，导致积累活性氧。总之，我们的研究结果阐明了 ISP-I 抗癌作用背后的多方面机制，强调了其作为 SCLC 治疗的有前途的候选药物的潜力。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Small cell lung cancer (SCLC) urgently needs new therapeutic approaches. We found that the antibiotic-derived compound Isovalerylspiramycin I (ISP-I) has potent anti-tumor activity against SCLC cell lines H1048 and DMS53 both in vitro and in vivo. ISP-I induced apoptosis, G2/M phase cell cycle arrest, and mitochondrial respiratory chain dysfunction in both cell lines. Comprehensive RNA sequencing revealed that the anti-SCLC effects of ISP-I were primarily attributed to ATR/CHK1-mediated DNA damage response and PERK/eIF2α/ATF4/CHOP-mediated ER stress. Importantly, the induction of DNA damage, ER stress, and apoptosis by ISP-I was mitigated by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC), underscoring the critical role of ROS in the anti-SCLC mechanism of ISP-I. Moreover, ISP-I treatment induced immunogenic cell death (ICD) in SCLC cells, as evidenced by increased adenosine triphosphate (ATP) secretion, elevated release of high-mobility group box 1 (HMGB1), and enhanced exposure of calreticulin (CRT) on the cell surface. Additionally, network pharmacology analysis, combined with cellular thermal shift assay (CETSA) and cycloheximide (CHX) chase experiments, demonstrated that ISP-I acted as a ligand for apurinic/apyrimidinic endonuclease 1 (APEX1) and promoted its degradation, leading to the accumulation of ROS. In conclusion, our findings elucidate the multifaceted mechanisms underlying the anti-cancer effects of ISP-I, highlighting its potential as a promising therapeutic candidate for SCLC treatment.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.