Bafilomycin C1 induces G0/G1 cell-cycle arrest and mitochondrial-mediated apoptosis in human hepatocellular cancer SMMC7721 cells.

Abstract

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.

• Authors: Xiaoxiao Gao, Li Han, Nan Ding, Yu Mu, Peipei Guan, Caijuan Hu, Xueshi Huang
• Journal: The Journal of antibiotics (J Antibiot (Tokyo)) Vol. 71 Issue 9 Pg. 808-817 (09 2018) ISSN: 1881-1469 [Electronic] England
• PMID: 29752478 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• CCND3 protein, human
• CCNE1 protein, human
• CDKN1A protein, human
• Cyclin D3
• Cyclin E
• Cyclin-Dependent Kinase Inhibitor p21
• Macrolides
• Oncogene Proteins
• bafilomycin C1
• CDK2 protein, human
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin D3 (biosynthesis)
• Cyclin E (biosynthesis)
• Cyclin-Dependent Kinase 2 (biosynthesis)
• Cyclin-Dependent Kinase 4 (biosynthesis)
• Cyclin-Dependent Kinase 6 (biosynthesis)
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis)
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, pathology)
• Macrolides (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (metabolism)
• Mitochondrial Membranes (pathology)
• Oncogene Proteins (biosynthesis)
• Oxidative Stress (drug effects)
• Streptomyces (metabolism)
• Xenograft Model Antitumor Assays