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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244376 | GEO | 2023/10/10

REPOSITORIES: GEO

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Project description:Background Neuroendcrine carcinoma (NEC) of lung consists of small-cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). Although long-term outcomes of SCLC patients are usually poor, a few patients achieve long-term survivals. Prognostic factors in SCLC have not been fully elucidated. microRNAs (miRNAs) are known to negatively regulate gene expression and to be relevant to tumorigenesis, tumor classification and prognosis. Methods 63 samples (46 neuroendocrine carcinoma including 35 SCLC and 11 LCNEC, 4 adenocarcinoma, 5 squamous cell carcinoma and 8 normal lung) were obtained through surgical resection. miRNA expression in each sample was comprehensively investigated using miRNA microarray. Results Unsupervised hierarchial clustering classified the all NEC into two subgroups, group 1 and 2. Group 1 was felt into an independent branch that consisted of only NEC, whereas group 2 was included in a branch that contained both NEC and non-NEC. Compared with SCLC of group 1 (SCLC 1), SCLC of group 2 (SCLC 2) was a distinct subgroup with surprisingly good prognosis (0% v 79% survived for 5 years; p=0.007). Serum proGRP level was significantly lower in SCLC 2 than in SCLC 1 despite of similar tumor stages between the two groups. Among 12 cases treated by presurgical chemotherapy, PR:NC ratio was 6:3 in SCLC 1 and 2:1 in SCLC 2, suggesting no apparent difference of chemosensitivity. Histologically, distinction between both groups was difficult. Cox regression analysis demonstrated that three miRNA signature was correlated with survival of SCLC patients. These prognostic miRNAs were differentially expressed between SCLC 1 and 2, which were validated by quantitative real time RT-PCR. Bioinformatics analysis predicted that these miRNAs targeted not only genes involving with tumorigenesis but also genes associated with neuroendocrine function. Conclusion miRNA expression profiling identified a distinct subgroup of SCLC with favorable prognosis. This subgroup might have less neuroendocrine character than usual SCLC. All samples were tissue samples obtained by surgical resection. 35 samples of small-cell lung cancer were investigated. 11 samples of larege cell neuroendocrine cancer, 4 samples of adenocarcinoma, 5 samples of squamous cell carcinoma and 8 samples of normal lung were also included as reference.

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

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