PMC:4330249 / 11346-14981 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4330249","sourcedb":"PMC","sourceid":"4330249","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4330249","text":"Nimbolide Inhibits Cancer Cell Metastasis\nMetastasis is the process by which a cancer cell leaves the primary tumor, travels to a distant site via the circulatory system, and begins a secondary tumor. In order to metastasize, cancer cells must invade through the basement membrane and the extracellular matrix (ECM). Proteolysis of the ECM is an important step in metastasis, and the process is associated with the upregulated production and activity of several ECM-degrading proteases. The matrix metalloproteinases (MMPs) constitute a family of structurally related, zinc-dependent endopeptidases that are capable of degrading the protein components of the ECM and basement membrane and release growth factors from ECM stores [47, 48]. MMP activity is regulated by specific inhibitors, the tissue inhibitors of MMP (TIMPs). Activation of chemokines and the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system is also a central mediator of tumor-cell migration and invasion, and IGF-I signaling can influence the uPAR pathway.\nChemokines are chemotactic cytokines that cause the directed migration of leukocytes and are induced by inflammatory cytokines, growth factors, and pathogenic stimuli. Chemokine signaling results in the transcription of target genes that are involved in cell invasion, motility, and survival. The upregulation of chemokine molecules in tumor biology as compared with \"normal\" cells confers chemokines as \"a magic bullet,\" as targeting them can potentially hit cancer cells and their metastasis, leaving non-affected cells unharmed [49]. The expression of the chemokines CCL2, CXCL12, and CXCL8 and their receptors CCR2, CXCR1, CXCR2, and CXCR4 is significantly decreased in nimbolide-treated breast cancer cell lines [46].\nuPA is a serine protease that is involved in cancer progression, mainly invasion and metastasis [50]. uPA can be observed as a multifunctional protein that is involved in both proteolysis and signal transduction [51]. Recently, nimbolide has been shown to interfere with the expression of NF-κB-regulated proteins, like Bcl-2, cyclooxygenase 2, MMP-9, and VEGF, by inhibiting IKK. Therefore, it is likely that nimbolide will interfere with cell migration invasion and angiogenesis [29]. The neem limonoids azadirachtin and nimbolide inhibit hamster cheek pouch carcinogenesis by prevention of procarcinogen activation and oxidative DNA damage, upregulation of antioxidants and carcinogen detoxification enzymes, and inhibition of tumor invasion and angiogenesis [24]. The protein expression of MMP-2 and -9 is significantly decreased, and TIMP-2 expression is increased in nimbolide-treated breast cancer cells [46]. Other studies also reported that the protein expression and activity of MMP-2 and -9 were significantly decreased in myeloid leukemia cell lines [16] and colon cancer cells [29]. Limonoid-treated xenografts exhibited significant down-regulation in the expression of proteins involved in tumor cell survival (Bcl-2, Bcl-xL, c-IAP-1, survivin, and Mcl-1), proliferation (c-Myc and cyclin D1), invasion (MMP-9, intercellular adhesion molecule 1), metastasis (CXCR4), and angiogenesis (VEGF) [26]. The migration and invasive potential of the MCF-7 and MDA-MB-231 cell lines were considerably suppressed upon nimbolide treatment. The results showed that nimbolide downregulated the expression of uPA, uPAR, chemokines, phopho-epidermal growth factor receptor, vascular endothelial growth factor, NF-κB, IKKα, IKKβ, MMP-2, and MMP-9 and upregulated the expression of TIMP-2, suggesting that nimbolide inhibits angiogenesis and metastasis of breast cancer [46].","divisions":[{"label":"Title","span":{"begin":0,"end":41}}],"tracks":[{"project":"2_test","denotations":[{"id":"25705153-19030970-44841362","span":{"begin":729,"end":731},"obj":"19030970"},{"id":"25705153-20470890-44841363","span":{"begin":733,"end":735},"obj":"20470890"},{"id":"25705153-15229479-44841364","span":{"begin":1573,"end":1575},"obj":"15229479"},{"id":"25705153-25377085-44841365","span":{"begin":1759,"end":1761},"obj":"25377085"},{"id":"25705153-23201006-44841366","span":{"begin":1861,"end":1863},"obj":"23201006"},{"id":"25705153-17409440-44841367","span":{"begin":1977,"end":1979},"obj":"17409440"},{"id":"25705153-21678498-44841368","span":{"begin":2246,"end":2248},"obj":"21678498"},{"id":"25705153-19391054-44841369","span":{"begin":2527,"end":2529},"obj":"19391054"},{"id":"25705153-25377085-44841370","span":{"begin":2676,"end":2678},"obj":"25377085"},{"id":"25705153-20829362-44841371","span":{"begin":2827,"end":2829},"obj":"20829362"},{"id":"25705153-21678498-44841372","span":{"begin":2855,"end":2857},"obj":"21678498"},{"id":"25705153-23766363-44841373","span":{"begin":3170,"end":3172},"obj":"23766363"},{"id":"25705153-25377085-44841374","span":{"begin":3631,"end":3633},"obj":"25377085"}],"attributes":[{"subj":"25705153-19030970-44841362","pred":"source","obj":"2_test"},{"subj":"25705153-20470890-44841363","pred":"source","obj":"2_test"},{"subj":"25705153-15229479-44841364","pred":"source","obj":"2_test"},{"subj":"25705153-25377085-44841365","pred":"source","obj":"2_test"},{"subj":"25705153-23201006-44841366","pred":"source","obj":"2_test"},{"subj":"25705153-17409440-44841367","pred":"source","obj":"2_test"},{"subj":"25705153-21678498-44841368","pred":"source","obj":"2_test"},{"subj":"25705153-19391054-44841369","pred":"source","obj":"2_test"},{"subj":"25705153-25377085-44841370","pred":"source","obj":"2_test"},{"subj":"25705153-20829362-44841371","pred":"source","obj":"2_test"},{"subj":"25705153-21678498-44841372","pred":"source","obj":"2_test"},{"subj":"25705153-23766363-44841373","pred":"source","obj":"2_test"},{"subj":"25705153-25377085-44841374","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93a2ec","default":true}]}]}}