The impact of exogenous CO releasing molecule CORM‑2 on inflammation and signaling of orthotopic lung cancer

Abstract

The present study aimed to evaluate the therapeutic effect of CO-releasing molecule-2 (CORM-2) in an established mouse orthotopic lung cancer model and investigate the underlying mechanism associated with inflammation pathway. A total of 80 mice were randomly divided into two groups with 20 serving as a normal control and 60 used for the orthotopic lung cancer model. The tumor group was either untreated, or administrated with DMSO or CORM-2. The mice were sacrificed at day 7 and 14 post-treatment, and the body weight, and thymus and spleen indices were determined. Pathological analysis was performed with hematoxylin and eosin (HE) staining. Serous inflammatory factors were measured using an ELISA. The expression levels of eukaryotic translation initiation factor 4E, p70S6K and toll-like receptor-4 (TLR4) were quantified by reverse transcription-polymerase chain reaction. The effects of CORM-2 on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), TLR4/nuclear factor (NF)-κB signaling pathways were determined by western blotting. The body weight increased over time in the control group, while it significantly declined in tumor-bearing mice (P<0.05). CORM-2 treatment significantly increased body weight in comparison with the model and DSMO treatment groups (P<0.05). The thymus and spleen indices both reduced in the model and DMSO treatment groups, which was significantly rescued with CORM-2 administration (P<0.05). The HE staining results demonstrated few nodule formations, fibrous hyperplasia and extensive necrosis, which suggested overt inhibitory effects against cancer of CORM-2. The serous contents of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 in the CORM-2 group was significantly lower compared with that in the model and DMSO groups (P<0.05). The ratio of phosphorylated (p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, p-NF-κB-p65/NF-κB-p65 and expression of TLR4 significantly decreased in the CORM-2 group compared with the model and DMSO groups (P<0.05). To the best of our knowledge, the data in the present study demonstrated in vivo for the first time, the therapeutic potential of the CORM complex, which is associated with suppression of inflammation and general protein synthesis.