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Background: Evidence is growing for beneficial interactions between omega-3 fatty acids from fish and chemotherapy agents in certain human cancers. Evidence for similar effects in prostate cancer is lacking. We investigated the effects of docosahexaenoic acid (DHA-22:6n-3), a component of fish oil, on the cytotoxicity of docetaxel in prostate cancer cells., Methods: Cell viability was studied using the MTT assay and apoptosis was evaluated by flow cytometry using PI, annexin V, and JC-1 staining. Cellular signaling mechanisms that might explain the observed pro-apoptotic effects were investigated using NF-kappaB pathway specific cDNA microarrays and RT-PCR validation., Results: DHA enhanced the pro-apoptotic efficacy of docetaxel, synergistically, in hormone receptor positive and negative LNCaP, DU145 and PC3 cells, respectively. Cell cycle analysis showed an increase in G2M arrest and JC-1 staining showed a significant (P < 0.018) increase in apoptotic cells with combination treatments in LNCaP cells. Microarray and RTPCR showed decreased expression of FADD, AKT1, MAX, TRAF3, MAP2k4, TNFRSF11A, and RIPK1 in LNCaP cells. Similar results were obtained with DU145 cells; combinations were more effective than single treatments. Combination treatments suppressed NF-kappaB signaling that was induced by docetaxel alone; this is considered an anti-apoptotic response., Conclusion: DHA synergistically enhanced the cytotoxic effect of docetaxel in prostate cancer cells through increased apoptosis by suppression of genes involved in the NF-kappaB pathway. This highlights the possibility of developing such combination modalities for treatment of prostate cancer., ((c) 2008 Wiley-Liss, Inc.)

Background: Conjugated linoleic acids (CLAs) have anti-tumorigenic properties in animal models and anti-proliferative effects on cancer cells in vitro. Previous studies have shown that the NF-kappaB pathway is involved regulating anti-apoptotic gene expression. The present study investigated the effects of CLAs (cis-9, trans-11, and trans-10, cis-12 isomers and a 50:50 mixture) on apoptosis and NF-kappaB activation in LNCaP cells., Methods: Apoptosis was assessed by annexin V staining using flow cytometry. TNF-alpha-induced NF-kappaB activity was determined by gel shift and reporter gene assays in addition to monitoring IkappaBalpha phosphorylation., Results: Only the CLA cis-9, trans-11 isomer significantly increased TNF-alpha-induced apoptosis (by 59%), which correlated with a reduction in NF-kappaB transcriptional activity (by 35%, P < 0.05), NF-kappaB binding activity (by 15%, P < 0.05), and phosphorylation of IkappaBalpha (by 36%, P < 0.01)., Conclusions: Our results may offer a mechanistic explanation for the reported inhibition of prostate tumor growth by CLAs in animal models of disease.

Conjugated linoleic acid (CLA) reduces mammary tumorigenesis in rodent models, induces apoptosis in rodent mammary tumor cell lines, and decreases expression of antiapoptotic bcl-2 in rat mammary tissue. This investigation focused on the cell mechanisms underlying the antitumor effects of CLA. Changes (mRNA, protein) in expression of major proapoptotic p53, p21WAF1/CIP1, bax, bcl-Xs genes, and the antiapoptotic bcl-2 gene were observed in malignant MCF-7 and MDA-MB-231 cells and in benign MCF-10a human mammary tumor cells in culture. CLA, but not linoleic acid (LA), inhibited proliferation in all cells; CLA mix was most effective. CLA increased DNA damage (apoptosis). CLA increased mRNA expression of p53 and p21WAF1/CIP1 (three- to fivefold and twofold, respectively) but either decreased bcl-2 by 20-30% or had no effect in MCF-7 and MCF-10a cells, respectively; protein expression reflected mRNA values. In MDA-MBA-231 (mutant p53) cells, mRNA for p53 was not changed, but p21WAF1/CIP1 and bcl-2 mRNA was increased. Protein expression largely reflected mRNA changes but, surprisingly, CLA completely suppressed mutant p53 protein in MDA-MB-231 cells. Apparent antiapoptotic effects of increased bcl-2 expression in MDA-MBA-231 cells were countered by increased proapoptotic p21WAF1/CIP1, Bax, and Bcl-Xs proteins. Findings indicate that CLA elicits mainly proapoptotic effects in human breast tumor cells through both p53-dependent and p53-independent pathways, according to cell type.

Abstract: Prostate cancer is the second most common cancer in men. The disease etiology is poorly understood, but diet and lifestyle are contributory factors. Conjugated linoleic acids (CLAs), naturally occurring fatty acids in ruminant food products, have antitumor properties in animal models of cancer and antiproliferative effects on cancer cells in vitro. The cellular mechanisms by which CLAs elicit these effects are unclear, particularly for prostate cancer cells. We have previously identified protein kinase C (PKC) isoformsα,δ,ι,μ, andζ in LNCaP prostate cancer cells. The objective of this study was to determine the effects of CLAs (individual cis-9, trans-11 and trans-10, cis-12 isoforms and a 50:50 mixture) on PKC isoform abundance in LNCaP cells. Confluent cells were treated with 6, 25, and 50μM CLA for 0.5, 6, and 24 h. Cytosol and membrane protein fractions were assayed for PKC isoforms (mainlyα andδ but alsoι,μ, andζ) by Western blot analysis using specific antibodies. CLAs clearly modulated the abundance of these PKC isoforms, both positively and negatively, depending on the isoform, concentration of CLAs, and period of treatment. Increased PKC-δ and decreased PKC-ι membrane abundance was consistent with CLAs eliciting increased apoptosis and, in part, with their antitumor effects. [ABSTRACT FROM AUTHOR]