oxepins and Cell-Transformation--Neoplastic

Physciosporin (PHY) is one of the potent anticancer lichen compound. Recently, PHY was shown to suppress colorectal cancer cell proliferation, motility, and tumorigenesis through novel mechanisms of action.. We investigated the effects of PHY on energy metabolism and tumorigenicity of the human breast cancer (BC) cells MCF-7 (estrogen and progesterone positive BC) and MDA-MB-231 (triple negative BC).. The anticancer effect of PHY on cell viability, motility, cancer metabolism and tumorigenicity was evaluated by MTT assay, migration assay, clonogenic assay, anchorage-independent colony formation assay, glycolytic and mitochondrial metabolism analysis, qRT-PCR, flow cytometric analysis, Western blotting, immunohistochemistry in vitro; and by tumorigenicity study with orthotopic breast cancer xenograft model in vivo.. PHY markedly inhibited BC cell viability. Cell-cycle profiling and Annexin V-FITC/PI double staining showed that a toxic dosage of PHY triggered apoptosis in BC cell lines by regulating the B-cell lymphoma-2 (Bcl-2) family proteins and the activity of caspase pathway. At non-toxic concentrations, PHY potently decreased migration, proliferation, and tumorigenesis of BC cells in vitro. Metabolic studies revealed that PHY treatment significantly reduced the bioenergetic profile by decreasing respiration, ATP production, and glycolysis capacity. In addition, PHY significantly altered the levels of mitochondrial (PGC-1α) and glycolysis (GLUT1, HK2 and PKM2) markers, and downregulated transcriptional regulators involved in cancer cell metabolism, including β-catenin, c-Myc, HIF-1α, and NF-κB. An orthotopic implantation mouse model of BC confirmed that PHY treatment suppressed BC growth in vivo and target genes were consistently suppressed in tumor specimens.. The findings from our in vitro as well as in vivo studies exhibit that PHY suppresses energy metabolism as well as tumorigenesis in BC. Especially, PHY represents a promising therapeutic effect against hormone-insensitive BC (triple negative) by targeting energy metabolism.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Female; Glycolysis; Humans; Mice; Oxepins; Triple Negative Breast Neoplasms

Lichens, which represent symbiotic associations of fungi and algae, are potential sources of numerous natural products. Physciosporin (PHY) is a potent secondary metabolite found in lichens and was recently reported to inhibit the motility of lung cancer cells via novel mechanisms.. The present study investigated the anticancer potential of PHY on colorectal cancer (CRC) cells.. PHY was isolated from lichen extract by preparative TLC. The effect of PHY on cell viability, motility and tumourigenicity was elucidated by MTT assay, hoechst staining, flow cytometric analysis, transwell invasion and migration assay, soft agar colony formation assay, Western blotting, qRT-PCR and PCR array in vitro as well as tumorigenicity study in vivo.. PHY decreased the viability of various CRC cell lines (Caco2, CT26, DLD1, HCT116 and SW620). Moreover, PHY elicited cytotoxic effects by inducing apoptosis at toxic concentrations. At non-toxic concentrations, PHY dose-dependently suppressed the invasion, migration and colony formation of CRC cells. PHY inhibited the motility of CRC cells by suppressing epithelial-mesenchymal transition and downregulating actin-based motility markers. In addition, PHY downregulated β-catenin and its downstream target genes cyclin-D1 and c-Myc. Moreover, PHY modulated KAI1 C-terminal-interacting tetraspanin and KAI1 expression, and downregulated the downstream transcription factors c-jun and c-fos. Finally, PHY administration showed considerable bioavailability and effectively decreased the growth of CRC xenografts in mice without causing toxicity.. PHY suppresses the growth and motility of CRC cells via novel mechanisms.

Topics: Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Lichens; Male; Mice, Inbred BALB C; Oxepins; Xenograft Model Antitumor Assays

Topics: Animals; Benzene Derivatives; Biotransformation; Carcinogens; Cell Transformation, Neoplastic; Cells, Cultured; Cricetinae; Cytochrome P-450 Enzyme System; Ethers, Cyclic; Glutathione; Isomerism; Liver; Macromolecular Substances; Mice; Mutagens; Naphthalenes; Oxepins; Oxides; Phenols; Polycyclic Compounds; Protein Binding; Rats