Epidemiological studies have linked fish oil consumption to a decreased incidence of cancer. The anticancer effects of fish oil are mostly attributed to its content of omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, DHA, because of its unique effect of altering membrane composition, is often regarded as the major omega-3 fatty acid involved in anticancer activity. Although use of DHA as an anticancer drug to prevent or treat human cancer in clinical settings has not yet been well established, recent studies suggest that DHA can be very effective as an adjuvant with other anticancer agents. In this article, we present studies that show the role of DHA in improving anticancer drug efficacy. Several in vitro and animal studies suggest that combining DHA with other anticancer agents often improves efficacy of anticancer drugs and also reduces therapy-associated side effects. Incorporation of DHA in cellular membranes improves drug uptake, whereas increased lipid peroxidation is another mechanism for DHA-mediated enhanced efficacy of anticancer drugs. In addition, several intracellular targets including cyclooxygenase-2, nuclear factor kappa B, peroxisome proliferator-activated receptor gamma, mitogen-activated protein kinase, AKT, and BCL-2/BAX are found to play an important role in DHA-mediated additive or synergistic interaction with anticancer drugs. The data suggest that DHA is a safe, natural compound that can greatly improve the anticancer properties of anticancer drugs. Use of DHA with anticancer treatments provides an avenue to therapeutic improvement that involves less risk or side effects for patients and reduced regulatory burden for implementation.

CXCL12/stromal cell-derived factor 1 is a member of the CXC family of chemokines that plays an important role in hematopoiesis and signals through CXCR4 and CXCR7. Two splice variants of human CXCL12 (CXCL12␣ and CXCL12␤) induce chemotaxis of CXCR4 ؉ cells and inhibit X4 infection. Recent studies described four other novel splice variants of human CXCL12; however, their antiviral activities were not investigated. We constructed and expressed all of the CXCL12 splice variants in Escherichia coli. Recombinant proteins were purified through a His affinity column, and their biological properties were analyzed. All six CXCL12 variants induced chemotaxis of CXCR4؉ and CXCR7 ؉ cell lines. Enhancement of survival and replating capacity of human hematopoietic progenitor cells were observed with CXCL12␣, CXCL12␤, and CXCL12 but not with the other variants. CXCL12␥ showed the greatest antiviral activity in X4 inhibition assays and the weakest chemotaxis activity through CXCR4. The order of potency in X4 inhibition assays was as follows: CXCL12␥ > CXCL12␤ > CXCL12␣ > CXCL12 > CXCL12 > CXCL12␦. The order of anti-human immunodeficiency virus (HIV) activity was associated with the number of BBXB motifs present in each variant; the most potent inhibitor was CXCL12␥, with five BBXB domains. The results suggest that the different C termini of CXCL12 variants may contain important molecular determinants for the observed differences in antiviral effects and other biological functions. These studies implicate CXCL12␥ as a potent HIV-1 entry inhibitor with significantly reduced chemotaxis activity and small or absent effects on progenitor cell survival or replating capacity, providing important insight into the structure-function relationships of CXCL12.Chemokines are small, structurally related chemoattractant cytokines, characterized by conserved cysteine residues. Based on the positions of the first N-terminal cysteines, chemokines fall into four subfamilies. The CC and CXC subfamilies have been well characterized. The CC subfamily includes RANTES (for "regulated on activation, normal T-cell expressed, and secreted"), MCP-1 (monocyte chemoattractant protein 1), and MIP-1␤ (macrophage inflammatory protein 1␤). The prototype of the CXC subfamily is interleukin-8 (IL-8). The C chemokine (lymphotactine) and the CX3C chemokine (fractalkine) subfamilies have been identified more recently (reviewed in reference 28). Chemokines signal through Gprotein-coupled seven-transmembrane-domain receptors and are primarily involved in immunosurveillance, activation, and recruitment of specific cell populations during disease (reviewed in reference 28).Stromal cell-derived factor 1 (SDF-1)/CXCL12 is a member of the CXC chemokine family and is a key regulator of B-cell lymphopoiesis, hematopoietic stem cell mobilization, and leukocyte migration (reviewed in reference 28). CXCL12 has also been shown to block human immunodeficiency virus type 1 (HIV-1) infection (reviewed in reference 38). CXCL12 was originally thought to mediate these processes throug...

BackgroundBreast cancer is a collection of diseases in which molecular phenotypes can act as both indicators and mediators of therapeutic strategy. Therefore, candidate therapeutics must be assessed in the context of multiple cell lines with known molecular phenotypes. Docosahexaenoic acid (DHA) and curcumin (CCM) are dietary compounds known to antagonize breast cancer cell proliferation. We report that these compounds in combination exert a variable antiproliferative effect across multiple breast cell lines, which is synergistic in SK-BR-3 cells and triggers cell signaling events not predicted by the activity of either compound alone.MethodsDose response curves for CCM and DHA were generated for five breast cell lines. Effects of the DHA+ CCM combination on cell proliferation were evaluated using varying concentrations, at a fixed ratio, of CCM and DHA based on their individual ED50. Detection of synergy was performed using nonlinear regression of a sigmoid dose response model and Combination Index approaches. Cell molecular network responses were investigated through whole genome microarray analysis of transcript level changes. Gene expression results were validated by RT-PCR, and western blot analysis was performed for potential signaling mediators. Cellular curcumin uptake, with and without DHA, was analyzed via flow cytometry and HPLC.ResultsCCM+DHA had an antiproliferative effect in SK-BR-3, MDA-MB-231, MDA-MB-361, MCF7 and MCF10AT cells. The effect was synergistic for SK-BR-3 (ER- PR- Her2+) relative to the two compounds individually. A whole genome microarray approach was used to investigate changes in gene expression for the synergistic effects of CCM+DHA in SK-BR-3 cells lines. CCM+DHA triggered transcript-level responses, in disease-relevant functional categories, that were largely non-overlapping with changes caused by CCM or DHA individually. Genes involved in cell cycle arrest, apoptosis, inhibition of metastasis, and cell adhesion were upregulated, whereas genes involved in cancer development and progression, metastasis, and cell cycle progression were downregulated. Cellular pools of PPARγ and phospho-p53 were increased by CCM+DHA relative to either compound alone. DHA enhanced cellular uptake of CCM in SK-BR-3 cells without significantly enhancing CCM uptake in other cell lines.ConclusionsThe combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon molecular phenotype. DHA enhancement of cellular curcumin uptake is one potential mechanism for observed synergy in SK-BR-3 cells; however, transcriptomic data show that the antiproliferation synergy accompanies many signaling events unique to the combined presence of the two compounds.

Metastasis is the leading cause of death from breast cancer. A major factor of metastasis is the migration of cancerous cells to other tissues by way of up-regulated chemokine receptors, such as CXCR4, on the cell surface.

BackgroundThe major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric, in an in vivo model of DMBA-induced mammary tumorigenesis in mice.MethodsWe used the carcinogen DMBA to induce breast tumors in SENCAR mice on control, CCM, DHA, or DHA + CCM diets. Appearance and tumor progression were monitored daily. The tumors were harvested 15 days following their first appearance for morphological and immunohistological analysis. Western analysis was performed to determine expression of maspin and survivin in the tumor tissues. Characterization of tumor growth was analyzed using appropriate statistical methods. Otherwise all other results are reported as mean ± SD and analyzed with one-way ANOVA and Tukey’s post hoc procedure.ResultsAnalysis of gene microarray data indicates that combined treatment with DHA + CCM altered the profile of “PAM50” genes in the SK-BR-3 cell line from an ER-/Her-2+ to that resembling a “normal-like” phenotype. The in vivo studies demonstrated that DHA + CCM treatment reduced the incidence of breast tumors, delayed tumor initiation, and reduced progression of tumor growth. Dietary treatment had no effect on breast size development, but tumors from mice on a control diet (untreated) were less differentiated than tumors from mice fed CCM or DHA + CCM diets. The synergistic effects also led to increased expression of the pro-apoptotic protein, maspin, but reduced expression of the anti-apoptotic protein, survivin.ConclusionsThe SK-BR-3 cells and DMBA-induced tumors, both with an ER- and Her-2+ phenotype, were affected by the synergistic interaction of DHA and CCM. This suggests that the specific breast cancer phenotype is an important factor for predicting efficacy of these nutraceuticals. The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon the molecular phenotype of the cancer.

We previously demonstrated that the naturally occurring splice variant stromal cell-derived factor 1␥/ CXCL12␥ is the most potent CXCL12 isoform in blocking X4 HIV-1, with weak chemotactic activity. A conserved BBXB domain (B for basic and X for any residue) located in the N terminus ( 24 KHLK 27 ) is found in all six isoforms of CXCL12. To determine whether the potent antiviral activity of CXCL12␥ is due to the presence of the extra C-terminal BBXB domains, we mutated each domain individually as well as in combination. Although binding of CXCL12␥ to heparan sulfate proteoglycan (HSPG) was 10-fold higher than that observed with CXCL12␣, the results did not demonstrate a direct correlation between HSPG binding and the potent antiviral activity. CXCL12␥ mutants lacking the conserved BBXB domain (designated ␥B1) showed increased binding to HSPG but reduced anti-HIV activity. In contrast, the mutants lacking the C-terminal second and/or third BBXB domain but retaining the conserved domain (designated B2, B3, and B23) showed decreased binding to HSPG but increased anti-HIV activity. The B2, B3, and B23 mutants were associated with enhanced CXCR4 binding, receptor internalization, and restored chemotaxis. Internalization of CXCR4 was more potent with CXCL12␥ than with CXCL12␣ and was significantly reduced when the conserved BBXB domain was mutated. We concluded that the observed potent anti-HIV-1 activity of CXCL12␥ is due to increased affinity for CXCR4 and to efficient receptor internalization.Chemokines are small, structurally related chemoattractant cytokines characterized by conserved cysteine residues. Based on the positions of the first N-terminal cysteines, chemokines fall into four subfamilies. The CC and CXC subfamilies have been well characterized. The CC subfamily includes the following: regulated on activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory peptides 1 (MIP-1). The prototype of the CXC subfamily is interleukin-8 (IL-8)/ CXCL8. The C chemokine (lymphotactine) and CX3C chemokine (fractalkine) subfamilies were recently identified (reviewed in reference 30). The physiological activities of chemokines are mediated by the selective recognition and activation of chemokine receptors belonging to the seven-membrane-domain G-protein-coupled receptor superfamily (GPCRs). In addition, chemokines also bind to glycosaminoglycans (GAGs) through distinct binding sites. Chemokine binding to GAGs on cells, particularly endothelial cells, results in chemotactic chemokine gradients that allow correct presentation of chemokines to leukocytes, therefore enabling target cells to cross the endothelial barrier and migrate into tissues (reviewed in reference 10).Stromal cell-derived factor 1 (SDF-1)/CXCL12 is a member of the CXC chemokine family and is a key regulator of B-cell lymphopoiesis, hematopoietic stem cell mobilization, and leukocyte migration (reviewed in reference 10). CXCL12 was originally thought to mediate these processes through...

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While PD0332991 is essentially cytostatic, inducing prolonged G1 arrest, it enhances the cytotoxic effect of other agents effective in MM, including bortezomib and lenalidomide, as confirmed in early phase clinical trials. However, with a plethora of other drugs of different classes being tested in MM, further development of PD0332991 will depend on defining the most efficacious combination with least toxicity. An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM. The next few years are likely to better define the place of PD0332991 in the treatment of MM.