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Review
. 2016 Jul 12;7(28):44790-44802.
doi: 10.18632/oncotarget.8316.

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development

Lingzhi Wang  1   2 , Do Dang Khoa Phan  1   3 , Jingwen Zhang  2 , Pei-Shi Ong  3 , Win Lwin Thuya  1   3 , Ross Soo  1   4 , Andrea Li-Ann Wong  1   4 , Wei Peng Yong  1   4 , Soo Chin Lee  1   4 , Paul Chi-Lui Ho  3 , Gautam Sethi  2 , Boon Cher Goh  1   2   4
Affiliations
Review

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development

Lingzhi Wang et al. Oncotarget. .

Abstract

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.

Keywords: anticancer property; nimbolide; pharmacodynamics; pharmacokinetics; toxicology.

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Conflict of interest statement

Conflicts of Interest: None declared.

Figures

Figure 1
Figure 1. A schematic illustration of the molecular mechanisms of the anticancer action of nimbolide [91]
Nimbolide induces apoptosis through diverse molecular mechanism(s). Nimbolide disrupts MOMP, which promotes caspases activation leading to apoptosis. Nimbolide also reduces the level of CDKs and cyclins, causing cell cycle arrest. Nimbolide also abrogates various signaling cascades including MAPK (ERK1/2), JAK2/STAT3 and PI3K/Akt, leading to suppression of proliferation of a wide variety of human cancer cells. Nimbolide disrupts the Nrf2-KEAP1 complex and promotes the release of Nrf2, thus increasing levels of antioxidant and detoxification enzymes. Nimbolide suppresses IκBα degradation and prevents nuclear translocation of p65, therefore repressing the expression of various genes involved in cell proliferation, anti-apoptosis, angiogenesis and metastasis. Inhibition of the NF-κB pathway also reduces the dissociation of GSK-3β from β-catenin, hence restraining the Wnt/β-catenin signaling pathway. →: activate/induce; Long Left Tack: suppress/inhibit.
Figure 2
Figure 2. The major anticancer activities and cancer preventive effect of nimbolide
See this image and copyright information in PMC

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