Cancer bush (CB, Sutherlandia frutescens), Devil's claw (DEV, Harpagophytum procumbens), Rooibos tea (RT, Aspalathus linearis), and Bambara groundnut (BB, Vignea subterranean) have been used to treat some malignancies and inflammatory disorders in Africa. However, biochemical basis for chemopreventive effects of these medicinal plants remains unclear. An abnormally elevated expression of cyclooxygenase-2 (COX-2) has been implicated in pathogenesis and progression of carcinogenesis. In the present study, we found that the methanol extracts of CB, DEV, RT, and BB inhibited, to a different extent, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced COX-2 expression in human breast epithelial (MCF10A) cells and in mouse skin in vivo. To determine the molecular mechanism of COX-2 inhibition by the above medicinal plants, we examined their effects on activation of NF-kappaB which is one of the major transcription factors responsible for regulating COX-2 expression. Methanol extracts of both CB and BB inhibited the DNA binding of NF-kappaB activated by TPA in MCF10A cells in a dose-dependent manner. Based on above findings, CB and BB are likely to inhibit TPA-induced COX-2 expression through suppression of DNA binding of NF-kappaB, which may contribute to the chemopreventive or chemoprotective activity of these African plants.
Cyclopentenone prostaglandins (cyPGs) are produced by dehydration of precursor molecules. The cyPGs are reported to have proapoptotic effects in a variety of cell types. However, cyPGs, particularly 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), can also exert cytoprotective effects at relatively low concentrations. The cytoprotective activity of cyPGs appears to be mediated by the reactive alpha,beta-unsaturated carbonyl group located in the cyclopentene ring. In this study, we investigated the effect of cyPGs on the expression of heme oxygenase-1 (HO-1), a ubiquitous stress-responsive enzyme that catalyzes oxidative cleavage of heme to form iron, carbon monoxide, and biliverdin. Treatment of the human breast cancer cell line (MCF-7) with 15d-PGJ(2) resulted in a concentration- and time-dependent increase in the expression of HO-1, whereas prostaglandin A(2) (PGA(2)) and the non-PG derivative 2-cyclopenten-1-one failed to induce HO-1 expression at the protein level. RT-PCR revealed that the expression of HO-1 mRNA was induced at 6 h by 15d-PGJ(2) at 10 microM. However, PGA(2) induced HO-1 mRNA expression at a higher concentration (30 microM). 2-Cyclopenten-1-one did not induce the expression of HO-1 mRNA at all. Likewise, 15d-PGJ(2) treatment for 6 h led to phosphorylation of Akt/protein kinase B (PKB) to a greater extent than that achieved with PGA(2). Thus, the induction of HO-1 expression and the activation of Akt/PKB by 15d-PGJ(2) and PGA(2) are likely to confer cytoprotective or antiapoptotic effects exerted by these cyPGs.
Lipids play important roles in maintaining membrane integrity and fluidity. Lipids, especially in the form of free fatty acids, are main sources of energy supply. Rapidly proliferating cancer cells have high avidity for energy, and this is met through elevated
de novo
synthesis of fatty acids that generate ATP during β‐oxidation process. It is evident that neoplastic tissues often exhibit aberrant activation of lipogenesis. Tumors reprogram signaling pathways via multiple mechanisms in the direction to meet the bioenergetic and biosynthetic demands. Now tumor‐associated reprogramming of lipid metabolism is recognized as one of the hallmarks of cancer. Some bioactive lipid metabolites, if produced in excess, influence the earlier stage of multistep carcinogenesis by damaging DNA or stimulating the mutated cells to premalignant ones during tumor promotion. Over the past decade, targeting aberrant lipid metabolism has become a promising anticancer or chemopreventive strategy.
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