PMC:4330249 / 5227-9713 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":"Inhibition of Cancer Cell Proliferation and Growth\nTumorigenesis and cancer progression are thought to be the result of some changes in different types of genetic pathways [27, 28]. Nimbolide, a chief constituent of neem, shows a vital role in cancer prevention and treatment through the modulation of various biological activities, including molecular cascades. However, understanding the mechanism of action of nimbolide in the activation or inactivation of genetic pathways will provide significant information to develop therapeutic approaches to manage various types of cancers.\nNimbolide induces in vitro cytotoxic activity against human cancer cell lines [20]. Nimbolide decreased cell viability, with an IC50 ranging from 4 to 10 µM and averaging 6 µM for the neuroblastoma (NE-115) and osteosarcoma (143B) cell lines [15]. Sastry et al. [21] have tested the in vitro cytotoxicity of nimbolide against a panel of human cancer cell lines. Treatment of cells with 0.5-5.0 µM nimbolide resulted in growth inhibition of the U937, HL-60, THP1, and B16 cell lines. It has been shown to interfere with the expression of cell survival proteins (Bcl-2, Bcl-xL, IAP-1, and IAP-2), proliferation (cyclin D1), invasion (matrix metalloproteinase [MMP]-9), and angiogenesis (vascular endothelial growth factor [VEGF]) by inhibiting inhibitor of κb (Iκb) kinase (IKK)/nuclear factor kappa B (NF-κB) [16]. Nimbolide treatment to human colon carcinoma (HT-29) cells at 2.5-10 µM resulted in moderate to very strong growth inhibition [29]. Nimbolide significantly inhibited cell viability, with IC50 values of 4.0 µM and 2.7 µM for 24 and 48 h, respectively, in MCF-7 cells and 6.0 µM and 3.2 µM for 24 and 48 h, respectively, in MDA-MB-231 cells [30].\nThe insulin-like growth factor (IGF) system is involved in the proliferation, survival, and migration of tumor cells. IGF-I receptor (IGF-IR) is a receptor tyrosine kinase that is overexpressed in about 70% of breast cancers [31, 32]. It is established that the consequences of IGF-IR activation by its ligands result in the recruitment of major adapter signaling proteins, such as src/collagen homology proteins, which lead to interaction with Grb2/Sos [33]. Recruitment of these molecules activates two distinct signal transduction pathways. One pathway activates Ras, Raf, and mitogen-activated protein kinase (MAPK), resulting in the transcription of genes that drive proliferation, and the other pathway involves phosphoinositide 3-kinase (PI3K)/Akt, which are responsible for cell survival and anti-apoptotic signal transduction [34]. Downregulation of these molecules will give rise to inhibition of cell survival, invasion, and induction of apoptosis.\nAberrant activation of PI3K/Akt signaling has been associated with the development and progression of many cancers [35], making this pathway an attractive target for therapeutic strategies. The increase in p-Akt level in breast tumor samples correlates with a poor prognosis [36, 37] and predicts a worse outcome among endocrine-treated patients [38]. The major inhibitor of Akt is the dual-specificity protein and lipid phosphatase, phosphatase tensin homolog deleted on chromosome 10 (PTEN) that counteracts the PI3K-dependent Akt activation by dephosphorylating the D3 position of PIP3 [39]. PTEN activity is frequently lost by mutations, deletions or promoter methylation silencing in many primary and metastatic human cancers [40, 41]. The inhibition of PI3K/Akt and activation of the PTEN pathway constitute a good strategy in the prevention of cancer.\nThe recent findings of Karkare et al. [42] proved that nimbolide suppresses glioblastoma viability and detains tumor growth by inhibiting CDK4/6 activity, leading to retinoblastoma hypophosphorylation and cell cycle arrest and by inhibiting growth factor pathways that are hyperactivated in glioblastoma, including the PI3K-Akt, MAPK, and JAK-STAT pathways [42]. It has been reported that decreased IGF-IRβ expression and increased IGFBP-3 expression are observed in nimbolide-treated breast cancer cells. The protein expression of the IGF signaling molecules IRS-2, PI3K, pAkt, Ras, Raf, MEK, and MAPK was significantly decreased in nimbolide-treated cells. This is further supported by a significant increase in the protein expression of PTEN upon nimbolide treatment in breast cancer cell lines (Fig. 3). Thereby, nimbolide inhibits the cell survival and proliferation of breast cancer and prostate cancer cells [19, 43].","divisions":[{"label":"Title","span":{"begin":0,"end":50}}],"tracks":[{"project":"2_test","denotations":[{"id":"25705153-25035775-44841334","span":{"begin":177,"end":179},"obj":"25035775"},{"id":"25705153-2614419-44841335","span":{"begin":663,"end":665},"obj":"2614419"},{"id":"25705153-8622560-44841336","span":{"begin":827,"end":829},"obj":"8622560"},{"id":"25705153-16793266-44841337","span":{"begin":847,"end":849},"obj":"16793266"},{"id":"25705153-20829362-44841338","span":{"begin":1393,"end":1395},"obj":"20829362"},{"id":"25705153-21678498-44841339","span":{"begin":1525,"end":1527},"obj":"21678498"},{"id":"25705153-23089555-44841340","span":{"begin":1738,"end":1740},"obj":"23089555"},{"id":"25705153-14729636-44841341","span":{"begin":1969,"end":1971},"obj":"14729636"},{"id":"25705153-14615489-44841342","span":{"begin":1973,"end":1975},"obj":"14615489"},{"id":"25705153-15229476-44841343","span":{"begin":2198,"end":2200},"obj":"15229476"},{"id":"25705153-17604717-44841344","span":{"begin":2579,"end":2581},"obj":"17604717"},{"id":"25705153-11882383-44841345","span":{"begin":2819,"end":2821},"obj":"11882383"},{"id":"25705153-16049961-44841346","span":{"begin":2979,"end":2981},"obj":"16049961"},{"id":"25705153-23535839-44841347","span":{"begin":2983,"end":2985},"obj":"23535839"},{"id":"25705153-11870534-44841348","span":{"begin":3050,"end":3052},"obj":"11870534"},{"id":"25705153-10656987-44841349","span":{"begin":3293,"end":3295},"obj":"10656987"},{"id":"25705153-9072974-44841350","span":{"begin":3435,"end":3437},"obj":"9072974"},{"id":"25705153-15382065-44841351","span":{"begin":3439,"end":3441},"obj":"15382065"},{"id":"25705153-24170547-44841352","span":{"begin":3601,"end":3603},"obj":"24170547"},{"id":"25705153-24170547-44841353","span":{"begin":3920,"end":3922},"obj":"24170547"},{"id":"25705153-24888707-44841354","span":{"begin":4478,"end":4480},"obj":"24888707"},{"id":"25705153-23963693-44841355","span":{"begin":4482,"end":4484},"obj":"23963693"}],"attributes":[{"subj":"25705153-25035775-44841334","pred":"source","obj":"2_test"},{"subj":"25705153-2614419-44841335","pred":"source","obj":"2_test"},{"subj":"25705153-8622560-44841336","pred":"source","obj":"2_test"},{"subj":"25705153-16793266-44841337","pred":"source","obj":"2_test"},{"subj":"25705153-20829362-44841338","pred":"source","obj":"2_test"},{"subj":"25705153-21678498-44841339","pred":"source","obj":"2_test"},{"subj":"25705153-23089555-44841340","pred":"source","obj":"2_test"},{"subj":"25705153-14729636-44841341","pred":"source","obj":"2_test"},{"subj":"25705153-14615489-44841342","pred":"source","obj":"2_test"},{"subj":"25705153-15229476-44841343","pred":"source","obj":"2_test"},{"subj":"25705153-17604717-44841344","pred":"source","obj":"2_test"},{"subj":"25705153-11882383-44841345","pred":"source","obj":"2_test"},{"subj":"25705153-16049961-44841346","pred":"source","obj":"2_test"},{"subj":"25705153-23535839-44841347","pred":"source","obj":"2_test"},{"subj":"25705153-11870534-44841348","pred":"source","obj":"2_test"},{"subj":"25705153-10656987-44841349","pred":"source","obj":"2_test"},{"subj":"25705153-9072974-44841350","pred":"source","obj":"2_test"},{"subj":"25705153-15382065-44841351","pred":"source","obj":"2_test"},{"subj":"25705153-24170547-44841352","pred":"source","obj":"2_test"},{"subj":"25705153-24170547-44841353","pred":"source","obj":"2_test"},{"subj":"25705153-24888707-44841354","pred":"source","obj":"2_test"},{"subj":"25705153-23963693-44841355","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93ecae","default":true}]}]}}