Manzamine A Exerts Anticancer Activity against Human Colorectal Cancer Cells

• Published in: Marine drugs 2018-07, Vol.16 (8), p.252
• Main Authors: Lin, Li-Chun, Kuo, Tzu-Ting, Chang, Hsin-Yi, Liu, Wen-Shan, Hsia, Shih-Min, Huang, Tsui-Chin
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antitumor activity; Apoptosis; Biocompatibility; Bioinformatics; Biological activity; Cancer; Caspase; Cell cycle; Cell death; Cell lines; Cell proliferation; Cells; Colorectal cancer; Colorectal carcinoma; Cyclin-dependent kinases; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA microarrays; DNA repair; E-cadherin; epithelial–mesenchymal transition; G1 phase; Gene expression; Interspecific relationships; Kinases; manzamine A; Marine invertebrates; Membrane potential; Mesenchyme; Metabolism; Metabolites; Metastases; Mitochondria; Mode of action; Neoplasms; Pancreas; Pancreatic cancer; Phenotypes; Predation; Proliferation; Secondary metabolites; Toxicity; Transcription factors; Tumor cell lines; Tumors
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md16080252

Marine sponges are known to produce numerous bioactive secondary metabolites as defense strategies to avoid predation. Manzamine A is a sponge-derived β-carboline-fused pentacyclic alkaloid with various bioactivities, including recently reported anticancer activity on pancreatic cancer. However, its cytotoxicity and mode of action against other tumors remain unclear. In this study, we exhibit that manzamine A reduced cell proliferation in several colorectal cancer (CRC) cell lines. To further investigate the manzamine A triggered molecular regulation, we analyzed the gene expression with microarray and revealed that pathways including cell cycle, DNA repair, mRNA metabolism, and apoptosis were dysregulated. We verified that manzamine A induced cell cycle arrest at G₀/G₁ phase via inhibition of cyclin-dependent kinases by p53/p21/p27 and triggered a caspase-dependent apoptotic cell death through mitochondrial membrane potential depletion. Additionally, we performed bioinformatics analysis and demonstrated that manzamine A abolished epithelial⁻mesenchymal transition process. Several mesenchymal transcriptional factors, such as Snail, Slug, and Twist were suppressed and epithelial marker E-cadherin was induced simultaneously in HCT116 cells by manzamine A, leading to the epithelial-like phenotype and suppression of migration. These findings suggest that manzamine A may serve as a starting point for the development of an anticancer drug for the treatment of metastatic CRC.