Novel Molecular Targets of Azadirachta indica Associated with Inhibition of Tumor Growth in Prostate Cancer

Abstract

Advanced prostate cancer has significant long-term morbidity, and there is a growing interest in alternative and complimentary forms of therapy that will improve the outcomes of patients. Azadirachta indica (common name: neem) contains multiple active compounds that have potent anti-inflammatory and anticancer properties. The present study investigates the novel targets of the anticancer activity of ethanol extract of neem leaves (EENL) in vitro and evaluates the in vivo efficacy in the prostate cancer models. Analysis of the components in the EENL by mass spectrometry suggests the presence of 2′,3′-dehydrosalannol, 6-desacetyl nimbinene, and nimolinone. Treatment of C4-2B and PC-3M-luc2 prostate cancer cells with EENL inhibited the cell proliferation. Genome-wide expression profiling, using oligonucleotide microarrays, revealed genes differentially expressed with EENL treatment in prostate cancer cells. Functional analysis unveiled that most of the up-regulated genes were associated with cell death, and drug metabolism, and the down-regulated genes were associated with cell cycle, DNA replication, recombination, and repair functions. Quantitative PCR confirmed significant up-regulation of 40 genes and immunoblotting revealed increase in the protein expression levels of HMOX1, AKR1C2, AKR1C3, and AKR1B10. EENL treatment inhibited the growth of C4-2B and PC-3M-luc2 prostate cancer xenografts in nude mice. The suppression of tumor growth is associated with the formation of hyalinized fibrous tumor tissue and the induction of cell death by apoptosis. These results suggest that EENL-containing natural bioactive compounds could have potent anticancer property and the regulation of multiple cellular pathways could exert pleiotrophic effects in prevention and treatment of prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1208/s12248-011-9279-4) contains supplementary material, which is available to authorized users.

Multi-constituent synergism is responsible for anti-inflammatory effect ofAzadirachta indicaleaf extract

“…In addition, the fractions also inhibited the activities of both COX-1 and COX-2, the enzymes essential for the prostaglandin synthesis (Kirkby et al, 2013). These findings are in agreement with some earlier reports on the in vitro inhibition of IL-1 and TNF-a production by neem extracts (Alam et al, 2012;Kaur et al, 2004;Mahapatra et al, 2011). However, a confirmatory in vivo test was imperatively needed to double check the observed in vitro effects, since the synthesis of cytokines in vivo may be affected by different physiological factors that are usually not present under in vitro conditions (Petrovsky & Harrison, 1995).…”

“…The anti-apoptotic, anti-proliferative, and immunomodulatory effects of the herb are reported (Kaur et al, 2004;Mahapatra et al, 2011;Schumacher et al, 2011), implying a potential anti-inflammatory activity. Several independent studies indicated the basic and preliminary evidences in support of its anti-inflammatory activity (Manogaran et al, 1998;Okpanyi & Ezeukwu, 1981).…”

Phytochemical Analysis and Antimicrobial Activity of Methanolic, Ethanolic and Acetonic Extracts of Stem Bark and Leaf of Neem Plant (<i>Azadirachta indica</i>)

“…Neem is an omnipotent tree and as acrid gift of nature. The A. indica is a very useful traditional medicinal plant in the African sub-continent and each part of the tree has some medicinal properties [19,1,8]. Neem tree is a tree in the mahogany family Meliaceae, is evergreen tree found in most tropical countries.…”

“…The secondary metabolites are used for medicine, flavourings and recreational drugs. These compounds after possible chemical manipulation provide and improved drugs to treat the infectious diseases [19].…”

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).…”