Nimbolide

The barks of Azadirachta indica

Nimbolide inhibits invasion and migration, and down-regulates uPAR chemokine gene expression, in two breast cancer cell lines.[Pubmed:25377085]

Cell Prolif. 2014 Dec;47(6):540-52.

OBJECTIVES: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women, worldwide. Urokinase type plasminogen activator (uPA) is a serine protease that is involved in cancer progression, especially invasion and metastasis of breast cancer. Nimbolide is a potent cytotoxic limnoid isolated from Azadirachta indica. Our previous studies have shown that Nimbolide elicits pleiotropic effects on breast cancer cells; however, its roles in invasion and migration have not previously been fully elucidated. MATERIALS AND METHODS: Protein expression of pEGFR, VEGFR, NFkappaB, IKKalpha, IKKbeta, MMP-2, MMP-9 and TIMP-2 were analysed by western blotting. We also analysed expressions of uPA, uPAR genes and chemokines by real-time PCR. Breast cancer cell invasion was assessed by transwell invasion assay and cell migration analysed by scratch wound healing assay. RESULTS: Our results showed that reduced protein expression of pEGFR, VEGFR, NFkappaB, IKKalpha, beta, MMP-2, MMP-9 and TIMP-2 was higher in Nimbolide-treated breast cancer cells. mRNA expression of uPA, uPAR, chemokines and their receptors were also significantly reduced in response to Nimbolide treatment. Nimbolide inhibited breast cancer cell migration and invasion as shown in transwell invasion and wound healing assays. CONCLUSION: These results clearly proved inhibitory effects of Nimbolide on tumour cell invasion and migration by down-regulating proteins critically involved in regulation of cell invasion and metastasis, suggesting a possible therapeutic role of Nimbolide for breast cancer.

Nimbolide attenuate the lipid accumulation, oxidative stress and antioxidant in primary hepatocytes.[Pubmed:29185131]

Mol Biol Rep. 2017 Dec;44(6):463-474.

Nimbolide is a bioactive compound found in Azadirachta indica. This work was devised to investigate the potential effects of Nimbolide on intracellular lipid deposition and its associated redox modulation in primary hepatocytes (Heps). Lipid accumulation was induced in Heps by supplementing 1 mM oleic acid for 24 h which was marked by significant accumulation of lipids. The results demonstrated that Nimbolide can decrease intracellular cholesterol, free fatty acids and triglycerides. Nimbolide may also improve hepatocytes function through its antioxidant effects by inhibiting oxidative DNA damage and lipid peroxidation by curtailing the reactive oxygen species levels. Further it also restore the mitochondrial potential, improving the endogenous antioxidant levels such as GSH and antioxidant enzyme activities. Nimbolide increased (P < 0.05) liver X receptor-alpha (LXRalpha), peroxisome proliferator-activated receptor-gamma (PPARgamma) and sterol regulatory element-binding protein-1c (SREBP1c) gene expression in Heps. The biological significance of Nimbolide may involve hypolipidemic effect, lipid peroxidation inhibition, DNA damage inhibition, ROS inhibition, restoring mitochondrial function, increases in GSH and SOD & CAT activities, and direct regulation of LXRalpha, PPARgamma and SREBP1c gene expression. Nimbolide may be used as effective lipid lowering compound and lipid deposition-induced Heps changes.

Modification of cysteine 179 of IkappaBalpha kinase by nimbolide leads to down-regulation of NF-kappaB-regulated cell survival and proliferative proteins and sensitization of tumor cells to chemotherapeutic agents.[Pubmed:20829362]

J Biol Chem. 2010 Nov 12;285(46):35406-17.

Reverse pharmacology, also called the "bedside to bench" approach, that deals with new uses for a well known molecular entity has been used extensively in cancer drug development to identify novel compounds and delineate their mechanisms of action. Here, we show that Nimbolide, a triterpenoid isolated from Azadirachta indica, enhanced the apoptosis induced by inflammatory cytokines and chemotherapeutic agents in tumor cells. This limonoid abrogated the expression of proteins associated with cell survival (Bcl-2, Bcl-xL, IAP-1, and IAP-2), proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF), all regulated by nuclear factor (NF)-kappaB. Nimbolide inhibited the activation of NF-kappaB induced by carcinogens and inflammatory stimuli. Constitutively active NF-kappaB found in most tumor cells was also inhibited. We found that suppression of NF-kappaB activation by Nimbolide was caused by inhibition of IkappaB kinase (IKK), which led to suppression of IkappaBalpha phosphorylation and degradation, nuclear translocation, DNA binding, and gene transcription. Reducing agent reversed the action of the limonoid, suggesting the involvement of a cysteine residue. Replacement of Cys(179) of IKK-beta with alanine abolished the effect of Nimbolide, suggesting that Cys(179) plays a critical role in inhibiting the NF-kappaB activation. Overall, our results indicate that Nimbolide can sensitize tumor cells to chemotherapeutic agents through interaction with IKK, leading to inhibition of NF-kappaB-regulated proteins.

The neem limonoids azadirachtin and nimbolide inhibit cell proliferation and induce apoptosis in an animal model of oral oncogenesis.[Pubmed:19458912]

Invest New Drugs. 2010 Aug;28(4):392-401.

Limonoids from the neem tree (Azadirachta indica) have attracted considerable research attention for their cytotoxicity against human cancer cell lines. However, the antiproliferative and apoptosis inducing effects of neem limonoids have not been tested in animal tumour models. The present study was therefore designed to evaluate the relative chemopreventive potential of the neem limonoids azadirachtin and Nimbolide in the hamster buccal pouch (HBP) carcinogenesis model by analyzing the expression of proliferating cell nuclear antigen (PCNA), p21(waf1), cyclin D1, glutathione S-transferase pi (GST-P), NF-kappaB, inhibitor of kappaB (IkappaB), p53, Fas, Bcl-2, Bax, Bid, Apaf-1, cytochrome C, survivin, caspases-3, -6, -8 and -9, and poly(ADP-ribose) polymerase (PARP) by RT-PCR, immunohistochemical, and Western blot analyses. The results provide compelling evidence that azadirachtin and Nimbolide mediate their antiproliferative effects by downregulating proteins involved in cell cycle progression and transduce apoptosis by both the intrinsic and extrinsic pathways. On a comparative basis, Nimbolide was found to be a more potent antiproliferative and apoptosis inducing agent and offers promise as a candidate agent in multitargeted prevention and treatment of cancer.

Nimbolide is a triterpene derived from the leaves and flowers of neem (Azadirachta indica L). Nimbolide induces apoptosis through inactivation of NF-κB. Nimbolide inhibits CDK4/CDK6 kinase activity. Nimbolide suppresses the NF-κB, Wnt, PI3K-Akt, MAPK and JAK-STAT signaling pathways.

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