Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP-2/9 expression via inhibiting ERK1/2 and reducing DNA-binding activity of NF-κB in colon cancer cells

• Published in: Molecular carcinogenesis Vol. 51; no. 6; pp. 475 - 490
• Main Authors: Babykutty, Suboj, P.S., Priya, R.J., Nandini, Kumar, M.A. Suresh, Nair, Mangalam S., Srinivas, Priya, Gopala, Srinivas
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.06.2012
• Subjects: Antineoplastic Agents - pharmacology; Caspases - metabolism; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; colon cancer; Colonic Neoplasms - enzymology; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Cyclin A - antagonists & inhibitors; Cyclin D1 - antagonists & inhibitors; Down-Regulation - drug effects; ERK1/2; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Gene Expression Regulation, Neoplastic - drug effects; Humans; invasion; JNK Mitogen-Activated Protein Kinases - metabolism; Limonins - chemistry; Limonins - pharmacology; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; MMP-2/9; Neoplasm Invasiveness; Neovascularization, Pathologic; NF-kappa B - metabolism; nimbolide; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Promoter Regions, Genetic - drug effects; RNA, Messenger - metabolism; Vascular Endothelial Growth Factor A - genetics
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.20812

Nimbolide, a plant‐derived limonoid has been shown to exert its antiproliferative effects in various cell lines. We demonstrate that nimbolide effectively inhibited proliferation of WiDr colon cancer cells through inhibition of cyclin A leading to S phase arrest. It also caused activation of caspase‐mediated apoptosis through the inhibition of ERK1/2 and activation of p38 and JNK1/2. Further nimbolide effectively retarded tumor cell migration and invasion through inhibition of metalloproteinase‐2/9 (MMP‐2/9) expression, both at the mRNA and protein level. It was also a strong inhibitor of VEGF expression, promoter activity, and in vitro angiogenesis. Finally, nimbolide suppressed the nuclear translocation of p65/p50 and DNA binding of NF‐κB, which is an important transcription factor for controlling MMP‐2/9 and VEGF gene expression. © 2011 Wiley Periodicals, Inc.