Effect of borrelidin on hepatocellular carcinoma cells in vitro and in vivo†
Hepatocellular carcinoma (HCC) is the most common type of liver cancer with high prevalence and mortality. Borrelidin, produced by several actinomycete bacteria of Streptomycin sp. exhibited diversiform activities including anti-bacterial, anti-viral, anti-angiogenic, and anti-tumor. However, the effect of borrelidin on HCC cells has not been characterized. The present study demonstrated borrelidin exhibited great potential to inhibit the growth of HCC cells, HepG2 and SMMC7721 in vitro. Western blot and real-time qPCR analysis revealed that borrelidin decreased the expressions of cyclin D1, cyclin D3, cyclin E1, CDK2, CDK4, and CDK6 and increased the expression of p21, thereby inducing G0/G1 cell cycle arrest. Moreover, borrelidin down-regulated expression of Bcl-2, up-regulated expression of Bax and increased cleavages of caspase-9 and caspase-3 to activate caspase-dependent apoptosis in HCC cells. Borrelidin inhibited migration and invasion through suppressing the expression of MMP-2 and MMP-9 in HCC cells. Further investigation indicated that the anti-tumor effect of borrelidin was mediated by MAPKs signaling pathway. In addition, an in vivo experiment revealed that borrelidin suppressed tumor growth in SMMC7721 xenograft model mice with few side effects. Cell cycle arrest and induced apoptosis were also observed in tumor tissues of model mice treated with borrelidin.