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

Abstract

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.

Preclinical Evaluation of the Supercritical Extract of Azadirachta Indica (Neem) Leaves In Vitro and In Vivo on Inhibition of Prostate Cancer Tumor Growth

“…More than 70 terpenoids have been identified in the neem plant (47, 48). To our knowledge, nimbolide is the only neem terpenoid reported to have anticancer activity (49, 50). In addition to nimbolide, our data reveal that the anticancer activity of other terpenoids from neem leaves, which includes nimbandiol, 2′,3′-dihydronimbolide, and 28-deoxynimbolide in prostate cancer cells (Table 1 and Supplementary Fig.…”

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development

“…for 10 days at a dose of 5mg/kg, a 67% reduction in the volume of colorectal cancer xenografts in mice was observed. At a higher dose of 20 mg/kg, an even more substantial and remarkable 90% reduction in tumour volume was achieved [13]. This was further accompanied by inhibition of angiogenesis and tumour metastasis, there by highlighting the promising activity of nimbolide against this cancer.…”

“…In addition, the anticancer and cancer preventive effects of nimbolide were observed in several animal studies [11–13], thereby providing strong evidence to support its further development as a therapeutic agent against cancer. In accordance with the drug development pipeline [14], nimbolide is now at the stage of preclinical pharmacological investigation, where pharmacodynamics (PD), toxicology, and pharmacokinetic (PK) studies should be performed before the drug can proceed to the clinical testing phase.…”

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

“…Over the past three decades, agents derived from natural sources have gained considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability (4). They have long been used in traditional Chinese medicine and show multiple biological activities, including anticancer, anti-inflammatory, and neuroprotective properties (5,6).…”