title: Cucurbitacin B inhibits breast cancer metastasis and angiogenesis through VEGF-mediated suppression of FAK/MMP-9 signaling axis.
abstract: Available breast cancer therapeutic strategies largely target the primary tumor but are ineffective against tumor metastasis and angiogenesis. In our current study, we determined the effect of Cucurbitacin B (CuB), a plant triterpenoid, on the metastatic and angiogenic potential of breast cancer cells. CuB was found to inhibit cellular proliferation and induce apoptosis in breast cancer cells in a time- and dose-dependent manner. Further, CuB-treatment significantly inhibited the migratory and invasive potential of highly metastatic breast cancer MDA-MB-231 and 4T1 cells at sub-IC50 concentrations, where no significant apoptosis was observed. CuB was also found to inhibit migratory, invasive and tube-forming capacities of HUVECs in vitro. In addition, inhibition of pre-existing vasculature in chick embryo chorioallantoic membrane ex vivo further supports the anti-angiogenic effect of CuB. CuB-mediated anti-metastatic and anti-angiogenic effects were associated with the downregulation of VEGF/FAK/MMP-9 signaling, which has been validated by using FAK-inhibitor (FI-14). CuB-treatment resulted in a significant inhibition of VEGF-induced phosphorylation of FAK and MMP-9 expressions similar to the action of FI-14. CuB was also found to decrease the micro-vessel density as evidenced by the decreased expression of CD31, a marker for neovasculature. Further, CuB-treatment inhibited tumor growth, lung metastasis and angiogenesis in a highly metastatic 4T1-syngeneic mouse mammary cancer. Collectively, our findings suggest that CuB inhibited breast cancer metastasis and angiogenesis, at least in part, through the downregulation of VEGF/FAK/MMP-9 signaling.
authors.affiliation: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Sajid
authors.initials: S
authors.lastname: Khan
authors.affiliation: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Samriddhi
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Amar Deep
authors.initials: AD
authors.lastname: Lakra
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Veterinary Medicine, Central Agricultural University, Selesih, Aizawl, Mizoram, India.
authors.forename: Gunjan
authors.initials: G
authors.lastname: Das
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.affiliation: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India. Electronic address: s.musthapa@cdri.res.in.
authors.forename: Syed Musthapa
authors.initials: SM
authors.lastname: Meeran
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; C041246:cucurbitacin B; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Angiogenesis; Breast cancer; Cancer prevention; Cucurbitacin B; Invasion; Metastasis