Abstract
Iturin A with cyclic peptide and fatty acid chain isolated from Bacillus subtilis fermentation shows a variety of biological activities. Among them, the anticancer activity attracted much attention. However, the molecular mechanism of its inhibitory effect on hepatocellular carcinoma was still unclear. Thus its effect on hepatocellular carcinoma was tested in this research. It was found that iturin A could enter HepG2 cells immediately and cause reactive oxygen species burst, disrupt cell cycle and induce apoptosis, paraptosis and autophagy in vitro. The iturin A without fatty acid chain showed no antitumor activity. Amphiphilic is critical to the activity of iturin A. The anticancer activity of iturin A to hepatocellular carcinoma was also verified in mice models carrying xenograft tumors constructed by HepG2 cells. At a dosage of 3 mg/kg/day, iturin A significantly inhibited the further increase of the tumor weight by 58.55%, and reduced the expression of Ki67 in tumor. In the tumor treated with iturin A, lymphocyte infiltration was found, and the expressions of TGF-β1and PD-L1 were decreased, which indicated that the tumor immune microenvironment was improved. Besides, iturin A showed no significant harm on the health of mice except slight disturbance of liver function. These results suggested that iturin A had significant antitumor effect in vitro and vivo, and provide a basis for the application of iturin A as anticancer agent.
Highlights
Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is the second-leading cause of cancer-related death globally (Chan and Ng 2020; Zucman-Rossi et al 2015)
Iturin A inhibits the growth of HepG2 cells by inducing apoptosis, autophagy and paraptosis Inhibition of HepG2 cell growth The results clearly showed iturin A treatment inhibited the growth of HepG2 cells in a concentration dependent manner
This indicated that iturin A treatment significantly promoted the occurrence of apoptosis, especially at the early stage in HepG2 cells
Summary
Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is the second-leading cause of cancer-related death globally (Chan and Ng 2020; Zucman-Rossi et al 2015). Many materials have been used to treat HCC, such as doxorubicin, cisplatin, 5-fluorouracil, doxorubicin, interferon, sorafenib and a number of other agents (Bruix et al 2019). It is critically needed to explore safe and efficient drugs for the therapy of HCC. The diversity of bioactive molecules in microbial metabolites provides a rich source of natural products for the exploration of new drugs. Bacillus subtilis is a nonpathogenic bacterium widely distributed in environment. Due to its abundant bioactive metabolites, B. subtilis is widely used in food preservation, agriculture, animal husbandry, medicine and so on(Guo et al 2017; Jiang
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