Bafilomycin C1, which was isolated from Streptomyces albolongus in our previous work, exhibited strong cytotoxicity against several cancer cell lines. This study aimed to evaluate its antitumor effect on human hepatocellular cancer SMMC7721 cells and the underlying mechanism in vitro and in vivo. MTT assay revealed that bafilomycin C1 retarded SMMC7721 cell growth and proliferation. Western blot and real-time qPCR analysis revealed that bafilomycin C1 caused partial G0/G1 phase cell-cycle arrest, downregulated the expression of cyclin D3, cyclin E1, CDK2, CDK4, and CDK6 and upregulated the expression of p21. Moreover, bafilomycin C1 caused mitochondrial membrane dysfunction through oxidative stress. Furthermore, bafilomycin C1 decreased the expression of Bcl-2; increased the expression of Bax, p53, and P-p53; and increased cleavage of caspase-9 and caspase-3, thereby inducing the intrinsic caspase-dependent apoptotic pathway. In vivo experiments in mice suggested that bafilomycin C1 suppressed tumor growth with few side effects. Cell-cycle arrest and induced apoptosis in tumor tissues in a mouse model treated with bafilomycin C1 were demonstrated by histological analyses, western blot and TUNEL. These findings indicate that bafilomycin C1 may be a promising candidate for hepatic cellular cancer therapy.

中文翻译：

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Bafilomycin C1在人肝细胞癌SMMC7721细胞中诱导G0 / G1细胞周期停滞和线粒体介导的凋亡。

在我们先前的研究中从长链链霉菌中分离出的巴菲洛霉素C1对多种癌细胞系表现出强大的细胞毒性。这项研究旨在评估其对人肝细胞癌SMMC7721细胞的抗肿瘤作用及其体内外机制。MTT分析表明，巴氟霉素C1抑制了SMMC7721细胞的生长和增殖。Western印迹和实时qPCR分析表明，巴氟霉素C1引起部分G0 / G1期细胞周期停滞，下调cyclin D3，cyclin E1，CDK2，CDK4和CDK6的表达，并上调p21的表达。此外，bafilomycin C1通过氧化应激导致线粒体膜功能障碍。此外，bafilomycin C1降低了Bcl-2的表达。增加Bax，p53和P-p53的表达；并增加了caspase-9和caspase-3的裂解，从而诱导了内在的caspase依赖性凋亡途径。小鼠体内实验表明，bafilomycin C1抑制肿瘤生长，几乎没有副作用。通过组织学分析，Western印迹和TUNEL证实了用巴氟霉素C1处理的小鼠模型中肿瘤组织的细胞周期停滞和诱导的凋亡。这些发现表明，bafilomycin C1可能是肝细胞癌治疗的有希望的候选者。