The neem limonoids azadirachtin and nimbolide inhibit cell proliferation and induce apoptosis in an animal model of oral oncogenesis

Kumar, G. Harish; Priyadarsini, Ramamurthi Vidya; Govindarajah, Vinothini; Letchoumy, P. Vidjaya; Nagini, Siddavaram

doi:10.1007/s10637-009-9263-3

Cited by 118 publications

(78 citation statements)

References 37 publications

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“…In agreement with these observations, nimbolide (10–100mg/kg) was shown to exhibit chemopreventive activity against 7,12-dimethylbenz[α]anthracene (DMBA)-induced oral carcinogenesis (50). In another hamster model of oral oncogenesis, the limonoid was shown to exhibit antiproliferative and apoptosis-inducing activities (33). Our study, however, is the first to demonstrate the potential of the limonoid in inhibiting the growth of CRC in a xenograft nude mouse model.…”

Section: Discussionmentioning

confidence: 99%

“…However, the limonoid has been shown to modulate numerous cell signaling molecules such as proliferating cell nuclear antigen (PCNA), p21, cyclin D1, glutathione S-transferase pi (GST-P), p53, Fas, Bcl-2, Bax, Bid, Apaf-1, cytochrome C, survivin, and caspases (33). The anticancer activities of nimbolide have been attributed to its α, β-unsaturated ketone structural element (34).…”

Section: Introductionmentioning

confidence: 99%

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Nimbolide, a Limonoid Triterpene, Inhibits Growth of Human Colorectal Cancer Xenografts by Suppressing the Proinflammatory Microenvironment

Gupta

Prasad

Sethumadhavan

et al. 2013

Clinical Cancer Research

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Purpose Extensive research over the past decade has revealed that the proinflammatory microenvironment plays a critical role in the development of colorectal cancer (CRC). Whether nimbolide, a limonoid triterpene, can inhibit the growth of CRC was investigated in the present study. Experimental Design The effect of nimbolide on proliferation of CRC cell lines was examined by MTT assay, apoptosis by caspase activation and poly-ADP ribose polymerase cleavage, nuclear factor-kappa B (NF-kB) activation by DNA-binding assay, and protein expression by Western blotting. The effect of nimbolide on the tumor growth in vivo was examined in CRC xenografts in a nude mouse model. Results Nimbolide inhibited proliferation, induced apoptosis, and suppressed NF-κB activation and NF-κB–regulated tumorigenic proteins in CRC cells. The suppression of NF-κB activation by nimbolide was caused by sequential inhibition of IκB kinase (IKK) activation, IκBα phosphorylation, and p65 nuclear translocation. Furthermore, the effect of nimbolide on IKK activity was found to be direct. In vivo, nimbolide (at 5 and 20 mg/kg body weight), injected intraperitoneally after tumor inoculation, significantly decreased the volume of CRC xenografts. The 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, Mcl-1), proliferation (c-Myc, cyclin D1), invasion (MMP-9, ICAM-1), metastasis (CXCR4), and angiogenesis (VEGF). The limonoid was found to be bioavailable in the blood plasma and tumor tissues of treated mice. Conclusions Our studies provide evidence that nimbolide can suppress the growth of human CRC through modulation of the proinflammatory microenvironment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nimbolide, a Limonoid Triterpene, Inhibits Growth of Human Colorectal Cancer Xenografts by Suppressing the Proinflammatory Microenvironment

Gupta

Prasad

Sethumadhavan

et al. 2013

Clinical Cancer Research

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“…Nimbolide was found to inhibit IκB degradation and prevent nuclear translocation of NF-κB. This subsequently caused cell cycle arrest by downregulating numerous genes involved in cellular proliferation [62]. Nimbolide can induce apoptosis through inactivation of NF-κB.…”

Section: Mechanism Of Actionsmentioning

confidence: 99%

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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“…The Anti-helminthic activity of NLE has also been reported in ruminents (Al-Rofaai et al 2012). One of the bioactive fractions of neem leaf (nimbolide) has anti-cancer property (Harish Kumar et al 2010). The apoptosis inducing ability of NLE has been investigated in cancer cells (Dharmalingam et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Neem (Azadirachta indica L.) leaf extract deteriorates oocyte quality by inducing ROS-mediated apoptosis in mammals

et al. 2014

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Neem (Azadirachta indica L.) leaf has been widely used in ayurvedic system of medicine for fertility regulation for a long time. The molecular mechanism by which neem leaf regulates female fertility remains poorly understood. Animal studies suggest that aqueous neem leaf extract (NLE) induces reactive oxygen species (ROS) - mediated granulosa cell apoptosis. Granulosa cell apoptosis deprives oocytes from nutrients, survival factors and cell cycle proteins required for the achievement of meiotic competency of follicular oocytes prior to ovulation. Under this situation, follicular oocyte becomes more susceptible towards apoptosis after ovulation. The increased level of hydrogen peroxide (H2O2) inside the follicular fluid results in the transfer of H2O2 from follicular fluid to the oocyte. The increased level of H2O2 induces p53 activation and over expression of Bax protein that modulates mitochondrial membrane potential and trigger cytochrome c release. The increased cytosolic cytochrome c level induces caspase-9 and caspase-3 activities that trigger destruction of structural and specific proteins leading to DNA fragmentation and thereby oocyte apoptosis. Based on these animal studies, we propose that NLE induces generation of ROS and mitochondria-mediated apoptosis both in granulosa cells as well as in follicular oocyte. The induction of apoptosis deteriorates oocyte quality and thereby limits reproductive outcome in mammals.

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The neem limonoids azadirachtin and nimbolide inhibit cell proliferation and induce apoptosis in an animal model of oral oncogenesis

Cited by 118 publications

References 37 publications

Nimbolide, a Limonoid Triterpene, Inhibits Growth of Human Colorectal Cancer Xenografts by Suppressing the Proinflammatory Microenvironment

Nimbolide, a Limonoid Triterpene, Inhibits Growth of Human Colorectal Cancer Xenografts by Suppressing the Proinflammatory Microenvironment

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development

Neem (Azadirachta indica L.) leaf extract deteriorates oocyte quality by inducing ROS-mediated apoptosis in mammals

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