Isovalerylspiramycin I suppresses non-small cell lung carcinoma growth through ROS-mediated inhibition of PI3K/AKT signaling pathway

Abstract

Novel drugs are required for non-small cell lung cancer (NSCLC) treatment urgently. Repurposing old drugs as new treatments is a practicable approach with time and cost savings. Some studies have shown that carrimycin, a Chinese Food and Drug Administration (CFDA)-approved macrolide antibiotic, possesses potent anti-tumor effects against oral squamous cell carcinoma. However, its detailed component and underlying mechanisms in anti-NSCLC remain unknown. In our study, isovalerylspiramycin I (ISP-I) was isolated from carrimycin and demonstrated a remarkable anti-NSCLC efficacy in vitro and in vivo with a favorable safety profile. It has been proven that in NSCLC cell lines H460 and A549, ISP-I could induce G2/M arrest and apoptosis, which was mainly attributed to ROS accumulation and subsequently PI3K/AKT signaling pathway inhibition. Numerous downstream genes including mTOR and FOXOs were also changed correspondingly. An observation of NAC-induced reverse effect on ISP-I-leading cell death and PI3K/AKT pathway inhibition, emphasized the necessity of ROS signaling in this event. Moreover, we identified ROS accumulation and PI3K/AKT pathway inhibition in tumor xenograft models in vivo as well. Taken together, our study firstly reveals that ISP-I is a novel ROS inducer and may act as a promising candidate with multi-target and low biological toxicity for anti-NSCLC treatment.

Effects of carrimycin on biomarkers of inflammation and immune function in tumor patients with sepsis: a multicenter double-blind randomized controlled trial

“…Carrimycin induces ROS accumulation by targeting the nucleolar protein selenoprotein H to trigger nucleolar stress and blocks ribosomal RNA transcription through the JNK2/TIF-IA/POLI pathway, leading to cell cycle arrest and apoptosis in cancer cells [10]. Carrimycin inhibits the growth of non-small cell lung cancer by inhibiting the PI3K/AKT signaling pathway by ROS [11] and inhibits the tumor growth of hepatocellular carcinoma in vitro and in vivo [12].…”

“…The mechanism of action of carrimycin is inhibition of protein synthesis by binding to bacterial ribosomes and it has a good effect on respiratory bacterial infections, and its clinical e cacy and safety are better than those of the placebo drug azithromycin [8]. Additionally, carrimycin exerts antitumor activity through various immune and in ammatory pathways [9][10][11][12].…”

Isovalerylspiramycin I inhibits proliferation, migration and invasion of osteosarcoma cells by targeting Topoisomerase 1 and suppressing the ataxia telangiectasia and Rad3‐related/checkpoint kinase 1 pathway

“…27,28 As a novel macrolide antibiotic, ISP-I also has been found to have potent antitumor effects in many malignancies. 20,29,30 The antitumor mechanisms of ISP-I differ greatly in different cancers. For example, ISP-I can reduce the expression of VEGF and PD-L1 in hepatocellular carcinoma cells.…”

“…29 ISP-I targets SELH and induces the accumulation of ROS and cancer cellspecific genomic instability in glioblastoma, 30 and causes ROS accumulation and inhibits the PI3K/AKT signalling pathway In non-small cell lung cancer. 20 Notably, ISP-I was proposed as a promising antitumor agent due to its unique multitarget ability, which may decrease the probability of chemotherapy resistance. 20 However, the effects of ISP-I on OS and the underlying mechanisms remain unexplored.…”

“…On the other hand, combined administration of ATR and/or CHEK1 inhibitors with TOP1 inhibitors has proven to be an ideal strategy to overcome drug resistance and enhance tumour-killing effects. [17][18][19] In this study, we demonstrate that isovalerylspiramycin I (ISP-I), the main active component of a novel macrolide antibiotic carrimycin approved by the China National Medical Products Administration, 20 exhibited significant antitumor activity in OS in vitro and in vivo. Mechanistically, TOP1 was identified and confirmed to be the direct target of ISP-I in OS.…”