The neem limonoids azadirachtin and nimbolide inhibit hamster cheek pouch carcinogenesis by modulating xenobiotic-metabolizing enzymes, DNA damage, antioxidants, invasion and angiogenesis

Abstract

The neem tree has attracted considerable research attention as a rich source of limonoids that have potent antioxidant and anti-cancer properties. The present study was designed to evaluate the chemopreventive potential of the neem limonoids azadirachtin and nimbolide based on in vitro antioxidant assays and in vivo inhibitory effects on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Both azadirachtin and nimbolide exhibited concentration-dependent anti-radical scavenging activity and reductive potential in the order: nimbolide > azadirachtin > ascorbate. Administration of both azadirachtin and nimbolide inhibited the development of DMBA-induced HBP carcinomas by influencing multiple mechanisms including prevention of procarcinogen activation and oxidative DNA damage, upregulation of antioxidant and carcinogen detoxification enzymes and inhibition of tumour invasion and angiogenesis. On a comparative basis, nimbolide was found to be a more potent antioxidant and chemopreventive agent and offers promise as a candidate agent in multitargeted prevention and treatment of cancer.

Modification of Cysteine 179 of IκBα Kinase by Nimbolide Leads to Down-regulation of NF-κB-regulated Cell Survival and Proliferative Proteins and Sensitization of Tumor Cells to Chemotherapeutic Agents

“…Down-regulation of the expression of the gene products involved in cell proliferation (c-Myc, cyclin D1, and COX-2) by nimbolide was concomitant with an inhibition of cell proliferation in various tumor cells. This result is further supported by a previous report that showed the ability of nimbolide to suppress the proliferation of a wide variety of cancer cells (12,18,19). In addition, the ability of nimbolide to suppress the TNF-␣-induced expression of ICAM-1 and MMP-9 suggests that it has a role in preventing metastasis and tumor invasion.…”

“…VEGF is a specific mitogen for vascular endothelial cells and is involved in carcinogenesis as an angiogenic factor. These results are in agreement with those of a recent report that demonstrated that this limonoid has anti-invasive and anti-angiogenic activities in cancer cells, although the mechanism by which this occurs has not been described (19).…”

Saffron Reduction of 7,12-Dimethylbenz[a]anthracene-induced Hamster Buccal Pouch Carcinogenesis

“…DMBA-induced hamster buccal pouch carcinogenesis is an accepted experimental animal model to test the chemopreventive potential of natural products and synthetic agents. Medicinal plants and their bioactive constituents exert their chemopreventive efficacy by modulating phase I and II detoxification cascade and improving antioxidant defense mechanism (Priyadarsini et al, 2009).…”

Herbal Antioxidants as Rejuvenators in Alternative Medicine

“…Increase in expression levels of HMOX1, AKR1C2, AKR1C3, and AKR1B10 was observed in prostate cancer cells after treatment with an ethanolic extract of neem leaves (Mahapatra et al, 2011). Inhibition of PC-3 cell proliferation and Bcl-2 expression was observed after neem treatment (Priyadarsini et al, 2009). A methanolic extract of neem leaves inhibited NF-κB activity in cultured human leukemia cells (Schumacher et al, 2011).…”