Effect Of Nimbolide Research Articles

Molecular Targets of Nimbolide for Anti-Cancer Therapy: An Updated Review

Cancer is a major cause of death worldwide with an increasing incidence rate and is considered a major public health problem. Distance metastasis to other tissues, high toxicity, and drug resistance of cancer cells to chemotherapy demand novel therapeutic approaches to treat cancer. Natural compounds from medicinal plants have been studied for therapeutic use in various malignancies. Nimbolide is an active principal compound from Azadirachta indica, which is an Asian traditional medicinal plant utilized historically as a remedy for a variety of diseases due to its antioxidant, anti-inflammatory, anti-cancer, and antimicrobial properties. It is a limonoid triterpene possessing potent anti-cancer effects in various types of cancers. It has been reported to induce multiple cytotoxic effects in tumor cells by modulating the cell proliferation, cell cycle, apoptosis, and metastasis by altering the various molecular signaling pathways. In the present review, we summarized all the in vitro and in vivo studies reporting the molecular targets of nimbolide for the therapeutic approaches in different types of cancer cells. We analyzed research publications up to September 2021 on the effect of nimbolide in various malignancies and the molecular mechanism of action. Nimbolide targets different signaling pathways including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), insulin like growth factor (IGF), Wingless and INT-1 (Wnt)/β-catenin, mitogen-activated protein kinases (MAPK)/c-Jun N-terminal kinases (JNK), phosphoinositide 3-kinase (PI3K)/AKT, tumor necrosis factor-α (TNF-α)/nuclear factor kappa B (NF-κβ), and death receptor 5 (DR5) in several cancer cells. Nimbolide's widespread availability and absence of side effects, as well as understanding the molecular mechanism of nimbolide's action, will be useful to develop a therapeutic agent against cancer.

Nimbolide Inhibits Nuclear Factor-КB Pathway in Intestinal Epithelial Cells and Macrophages and Alleviates Experimental Colitis in Mice.

Nimbolide is a limonoid extracted from neem tree (Azadirachta indica) that has antiinflammatory properties. The effect of nimbolide on the nuclear factor-kappa B (NF-κB) pathway in intestinal epithelial cells (IECs), macrophages and in murine colitis models was investigated. The IEC COLO 205, the murine macrophage cell line RAW 264.7, and peritoneal macrophages from interleukin-10-deficient (IL-10-/- ) mice were preconditioned with nimbolide and then stimulated with tumor necrosis factor-α (TNF-α) or lipopolysaccharide. Dextran sulfate sodium-induced acute colitis model and chronic colitis model in IL-10-/- mice were used for in vivo experiments. Nimbolide significantly suppressed the expression of inflammatory cytokines (IL-6, IL-8, IL-12, and TNF-α) and inhibited the phosphorylation of IκBα and the DNA-binding affinity of NF-κB in IECs and macrophages. Nimbolide ameliorated weight loss, colon shortening, disease activity index score, and histologic scores in dextran sulfate sodium colitis. It also improved histopathologic scores in the chronic colitis of IL-10-/- mice. Staining for phosphorylated IκBα was significantly decreased in the colon tissue after treatment with nimbolide in both models. Nimbolide inhibits NF-κB signaling in IECs and macrophages and ameliorates experimental colitis in mice. These results suggest nimbolide could be a potentially new treatment for inflammatory bowel disease. Copyright © 2016 John Wiley & Sons, Ltd.

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

Extensive research over the past decade has revealed that the proinflammatory microenvironment plays a critical role in the development of colorectal cancer. Whether nimbolide, a limonoid triterpene, can inhibit the growth of colorectal cancer was investigated in the present study. The effect of nimbolide on proliferation of colorectal cancer cell lines was examined by MTT assay, apoptosis by caspase activation and poly-ADP ribose polymerase cleavage, NF-κB activation by DNA-binding assay, and protein expression by Western blotting. The effect of nimbolide on the tumor growth in vivo was examined in colorectal cancer xenografts in a nude mouse model. Nimbolide inhibited proliferation, induced apoptosis, and suppressed NF-κB activation and NF-κB-regulated tumorigenic proteins in colorectal cancer 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 colorectal cancer xenografts. The limonoid-treated xenografts exhibited significant downregulation 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, ICAM-1), metastasis (CXCR4), and angiogenesis (VEGF). The limonoid was found to be bioavailable in the blood plasma and tumor tissues of treated mice. Our studies provide evidence that nimbolide can suppress the growth of human colorectal cancer through modulation of the proinflammatory microenvironment.

Abstract 166: A novel therapeutic approach for triple negative breast cancer

Abstract Triple negative breast cancers (TNBCs) are defined as tumors that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (EGFR2). TNBCs account for 15-20% of all breast tumors. These breast tumors are usually aggressive and have a specific molecular profile. Unfortunately, treatment options for TNBCs are limited, leading to a poor prognosis and high mortality rates. Thus, novel therapeutic approaches are needed to treat TNBCs. To date, several molecular targets have been identified (e.g., PARP, EGFR, mTOR, Akt, and BRAC-1). Moreover, many pre-clinical and clinical trials are underway to determine the efficacy of specific inhibitors against these molecular targets, used either alone or in combination with chemotherapeutic agents. So far, these trials have failed to produce significant promising results. Hence, our goal is to identify novel therapeutic agents that specifically target breast tumor cells, especially TNBCs, without causing toxicity to normal cells. Our studies identified nimbolide as a novel therapeutic agent. Nimbolide is a major bioactive compound derived from the Azadirachta indica (Neem) leaves, which is well-known medicinal plant having a wide spectrum of biological activities. In our studies, nimbolide targeted TNBC cells without causing toxicity to normal primary breast epithelial cells. We also explored the molecular mechanism underlying the anti-cancer effect of nimbolide on TNBC cells and found that nimbolide, simultaneously inhibited phosphorylation of Akt mediates pro-survival signaling. In addition, downstream signaling by mTOR and NF-kappa-B was down regulated by nimbolide which resulted in the induction of pJNK and pc-Jun mediated pro-apoptotic signaling and apoptosis in TNBC cells. These changes in the pro and anti-apoptotic molecular circuits also inhibited migration and invasion properties of TNBC cells. Altogether, our results strongly suggest that nimbolide could be a potent compound for the prevention and/or treatment of TNBC. Our ongoing in vivo studies may reveal the in vivo efficacy of nimbolide and toxicity to other organs or cells if any. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 166. doi:1538-7445.AM2012-166