Nimbolide inhibits invasion and migration, and down‐regulates uPAR chemokine gene expression, in two breast cancer cell lines

Elumalai, Perumal; Mercy, A. Brindha; Arunkamar, R.; Sharmila, Govindaraj; Bhat, Firdous Ahmad; Solaimuthu, Balakrishnan; Singh, Pratibha; Arunakaran, J.

doi:10.1111/cpr.12148

Cited by 28 publications

(47 citation statements)

References 52 publications

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“…The downregulation of proinvasive and angiogenic proteins, with up-regulationof their inhibitors by nimbolide that was observed in this study was in line with the anti-invasive and anti-angiogenic potential of neem preparations [70]. In addition, nimbolide reduced mRNA expression of MMP-2, MMP-9, uPA and uPA receptor in breast cancer cells (MCF-7) [30]. …”

Section: Mechanism Of Actionssupporting

confidence: 77%

“…Additionally, an in vitro study further indicated that nimbolide was able to combat metastasis and angiogenesis of cancer cells [29]. For instance, nimbolide have been shown to effectively decrease breast cancer cell invasion and migration via the transwell invasion and wound healing assays [30]. …”

Section: Anti-cancer Activitiesmentioning

confidence: 99%

“…CXCR4 is responsible for metastatic implantation into other organs [73]. For instance, nimbolide treatment (2, 4 μM in breast cancer MCF-7 cells) was found to significantly reduce CCL2, CXCR4, and CXCL12 mRNA expression compared to control cells [30]. Similarly, nimbolide was shown to downregulate the expression of MMP-9, ICAM-1, and CXCR4 in colorectal cancer xenografts in a nude mouse model [13].…”

Section: Mechanism Of Actionsmentioning

confidence: 99%

“…Moreover, CXCL8 or interleukin-8, a pro-angiogenic chemokine, can stimulate both endothelial cell proliferation and migration through CXCR2 as well as enhance VEGF production [73, 77]. Evidently, nimbolide also reduced expression of CXCL8 and CXCR2 in breast cancers, and thus abrogated angiogenesis [30]. …”

Section: Mechanism Of Actionsmentioning

confidence: 99%

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Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development

et al. 2016

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Nimbolide is one of the main components in the leaf extract of Azadirachta indica (A. indica). Accumulating evidence from various in vitro and in vivo studies indicates that nimbolide possesses potent anticancer activity against several types of cancer and also shows potential chemopreventive activity in animal models. The main mechanisms of action of nimbolide include anti-proliferation, induction of apoptosis, inhibition of metastasis and angiogenesis, and modulation of carcinogen-metabolizing enzymes. Although multiple pharmacodynamic (PD) studies have been carried out, nimbolide is still at the infant stage in the drug development pipeline due to the lack of systematic pharmacokinetic (PK) studies and long-term toxicological studies. Preclinical PK and toxicological studies are vital in determining the dosage range to support the safety of nimbolide for first-in-human clinical trials. In this review, we will provide a comprehensive summary for the current status of nimbolide as an anticancer and chemopreventive lead compound, and highlight the importance of systematic preclinical PK and toxicological studies in accelerating the process of application of nimbolide as a therapeutic agent against various malignancies.

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Section: Mechanism Of Actionssupporting

confidence: 77%

Section: Anti-cancer Activitiesmentioning

confidence: 99%

Section: Mechanism Of Actionsmentioning

confidence: 99%

Section: Mechanism Of Actionsmentioning

confidence: 99%

See 2 more Smart Citations

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development

et al. 2016

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“…Nimbolide has been shown to exert multiple therapeutic effects and possesses a cyclic enone capable of reacting with cysteines [10][11][12] . In the context of cancer, nimbolide has been shown to inhibit tumorigenesis and metastasis without causing any toxicity or unwanted side effects across a wide range of cancers 10,11,[13][14][15][16][17] . While previous studies suggest that nimbolide impairs cancer pathogenicity through modulating signaling pathways and transcription factors linked to survival, growth, invasion, angiogenesis, inflammation, and oxidative stress the direct targets of nimbolide still remain poorly characterized 10,15,[18][19][20][21][22] .…”

Section: Introductionmentioning

confidence: 99%

Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation

Spradlin

Ward

et al. 2018

Preprint

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Nimbolide, a terpenoid natural product derived from the Neem tree, impairs cancer pathogenicity across many types of human cancers; however, the direct targets and mechanisms by which nimbolide exerts its effects are poorly understood. Here, we used activity-based protein profiling (ABPP) chemoproteomic platforms to discover that nimbolide reacts with a novel functional cysteine crucial for substrate recognition in the E3 ubiquitin ligase RNF114. Nimbolide impairs breast cancer cell proliferation in-part by disrupting RNF114 substrate recognition, leading to inhibition of ubiquitination and degradation of the tumor-suppressors such as p21, resulting in their rapid stabilization. We further demonstrate that nimbolide can be harnessed to recruit RNF114 as an E3 ligase in targeted protein degradation applications and show that synthetically simpler scaffolds are also capable of accessing this unique reactive site. Our study highlights the utility of ABPP platforms in uncovering unique druggable modalities accessed by natural products for cancer therapy and targeted protein degradation applications.

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Limonoids from neem (Azadirachta indica A. Juss.) are potential anticancer drug candidates

Nagini,

Palrasu,

Bishayee

2023

Medicinal Research Reviews

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Neem (Azadirachta indica A. Juss.), a versatile evergreen tree recognized for its ethnopharmacological value, is a rich source of limonoids of the triterpenoid class, endowed with potent medicinal properties. Extracts of neem have been documented to display anticancer effects in diverse malignant cell lines as well as in preclinical animal models that has largely been attributed to the constituent limonoids. Of late, neem limonoids have become the cynosure of research attention as potential candidate agents for cancer prevention and therapy. Among the various limonoids found in neem, azadirachtin, epoxyazadiradione, gedunin, and nimbolide, have been extensively investigated for anticancer activity. Azadirachtin, a potent biodegradable pesticide, exhibits profound antiproliferative effects by preventing mitotic spindle formation and cell division. The antiproliferative activity of gedunin has been demonstrated to be mediated primarily via inhibition of heat shock protein90 and its client proteins. Epoxyazadiradione inhibits pro‐inflammatory and kinase‐driven signaling pathways to block tumorigenesis. Nimbolide, the most potent cytotoxic neem limonoid, inhibits the growth of cancer cells by regulating the phosphorylation of keystone kinases that drive oncogenic signaling besides modulating the epigenome. There is overwhelming evidence to indicate that neem limonoids exert anticancer effects by preventing the acquisition of hallmark traits of cancer, such as cell proliferation, apoptosis evasion, inflammation, invasion, angiogenesis, and drug resistance. Neem limonoids are value additions to the armamentarium of natural compounds that target aberrant oncogenic signaling to inhibit cancer development and progression.

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Nimbolide inhibits invasion and migration, and down‐regulates uPAR chemokine gene expression, in two breast cancer cell lines

Abstract: 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.

Cited by 28 publications

References 52 publications

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development

Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation

Limonoids from neem (Azadirachta indica A. Juss.) are potential anticancer drug candidates

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