Isovalerylspiramycin I suppresses small cell lung cancer growth via ROS-mediated DNA damage and ER Stress. Isovalerylspiramycin I suppresses small cell lung cancer growth via ROS-mediated DNA damage and ER Stress

Characterized by rapid progression, early metastasis, and poor prognosis, small cell lung cancer (SCLC) is a highly malignant tumor with limited treatment breakthroughs for nearly 30 years. Exploring alternative approaches is urgent. Tumor cells are more susceptible to ROS triggers for they have a fragile redox balance compared to normal cells. Isovalerylspiramycin I (ISP-I)， purified from a novel macrolide antibiotic carrimycin， inducing accumulation of ROS in several tumor cells, has shown impressive anti-tumor potential. While the specific details and mechanisms of ISP-I's anti-SCLC effects remain unrevealed. We demonstrated that, ISP-I inhibited SCLC growth dose-dependently in vitro and in vivo, with good safety profiles for showing low toxicity to normal cells (MRC-5) and mice at therapeutic doses. Then, we utilized SCLC cell lines H1048 and DMS53 to uncover the anti-SCLC mechanisms of ISP-I. Primarily, ISP-I acted as an inducer of ROS, leading to H1048 and DMS53 cells DNA damage and endoplasmic reticulum (ER) stress through ROS accumulation， ultimately resulting in tumor cells G2/M cell cycle arrest and apoptosis. In conclusion, our study has proven that ISP-I may be a promising therapeutic approach for SCLC with good safety profiles. Overall design: Total RNA from ISP-I (10μM) or DMSO (control) treated SCLC H1048 cells was extracted.And we usd the RNA to analyze the differentially expressed genes between the treatment groups and the control groups. Both groups were processed in 3 biological replicates.

小细胞肺癌（small cell lung cancer, SCLC）以进展迅速、早期转移、预后不良为典型特征，是一类恶性程度极高的肿瘤，近30年来其治疗领域鲜有突破性进展，探索新型治疗方案已成为迫切需求。肿瘤细胞相较于正常细胞氧化还原平衡更为脆弱，因而更易受到活性氧（Reactive Oxygen Species, ROS）介导的损伤。异戊酰螺旋霉素I（Isovalerylspiramycin I, ISP-I）是从新型大环内酯类抗生素（macrolide antibiotic）卡里霉素（carrimycin）中纯化得到的物质，可在多种肿瘤细胞中诱导活性氧积累，已展现出优异的抗肿瘤潜力，但其针对小细胞肺癌的具体作用细节与分子机制仍未阐明。本研究证实，ISP-I在体外与体内实验中均能以剂量依赖性方式抑制小细胞肺癌的生长；且在治疗剂量下，其对正常细胞（MRC-5）及小鼠的毒性较低，具备良好的安全性。随后，我们借助小细胞肺癌细胞系H1048与DMS53，深入解析ISP-I抗小细胞肺癌的分子机制：具体而言，ISP-I作为活性氧诱导剂，通过诱导活性氧积累致使H1048与DMS53细胞发生DNA损伤与内质网（endoplasmic reticulum, ER）应激，最终引发肿瘤细胞出现G2/M期细胞周期阻滞与凋亡。综上，本研究证实ISP-I有望成为一种安全性良好的小细胞肺癌潜在治疗策略。实验整体设计如下：提取经10μM ISP-I或二甲基亚砜（dimethyl sulfoxide, DMSO，对照组）处理的小细胞肺癌H1048细胞的总RNA，以此分析处理组与对照组间的差异表达基因；两组均设置3次生物学重复。