Manzamine A Exerts Anticancer Activity against Human Colorectal Cancer Cells.
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.
['Lin|Li-Chun|LC|', 'Kuo|Tzu-Ting|TT|', 'Chang|Hsin-Yi|HY|0000-0002-2742-0676', 'Liu|Wen-Shan|WS|', 'Hsia|Shih-Min|SM|0000-0003-2888-2618', 'Huang|Tsui-Chin|TC|0000-0001-7873-132X']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D002227:Carbazoles D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D015179:Colorectal Neoplasms D004353:Drug Evaluation, Preclinical D058750:Epithelial-Mesenchymal Transition D059585:G1 Phase Cell Cycle Checkpoints D020869:Gene Expression Profiling D006801:Humans D053078:Membrane Potential, Mitochondrial D020411:Oligonucleotide Array Sequence Analysis D011161:Porifera D015398:Signal Transduction
manzamine A colorectal cancer cell cycle apoptosis epithelial–mesenchymal transition