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. 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.