A synergistic antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells: unique signaling not explained by the effects of either compound alone

Abstract

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.

Nutrient-Gene Interaction in Colon Cancer, from the Membrane to Cellular Physiology

“…Moreover, curcumin is known to modulate DNA methylation in colorectal cancer cells (122), and recent advances in microarray and sequencing technologies have reported miRNA genes that are silenced by methylation in cancer (126). It has also been suggested that DHA enhances cell permissiveness to curcumin uptake (4, 137). Therefore, a diet containing both n-3 PUFA and curcumin may suppress colon cancer by acting on different molecular targets.…”

Emerging targets in lipid-based therapy

“…It is an anti-inflammatory agent and can sensitize existing chemotherapies. This synergism is likely due to its concomitant effect on both COX and LOX enzymes as well as cPLA2 phosphorylation, which has been described [158–160]. While curcumin can be consumed in great quantity without adverse effect, its bioavailability is limited [161].…”

“…Subsequently DHA was shown to target SOD1 in a PPARalpha dependent manner [201]. DHA also synergizes with and enhances curcumin activity against breast cancer cell proliferation [158]. …”

Evaluation of analgesic activity of turmeric (Curcuma longa Linn.) in Wister rats

“…It is found in the rhizome of the herb Curcuma longa Linn., which is commonly known as turmeric. 1 Turmeric is widely used in therapeutic preparations against anorexia, rhinitis, herpes zoster, acne, cough, urinary tract diseases, diabetic wounds, hepatic disorder, rheumatism and sinusitis. [1][2][3] Curcumin has several properties including antioxidant, antimicrobial, anti-inflammatory, antiviral, anti-carcinogenic and anti-diabetic activities.…”

“…1 Turmeric is widely used in therapeutic preparations against anorexia, rhinitis, herpes zoster, acne, cough, urinary tract diseases, diabetic wounds, hepatic disorder, rheumatism and sinusitis. [1][2][3] Curcumin has several properties including antioxidant, antimicrobial, anti-inflammatory, antiviral, anti-carcinogenic and anti-diabetic activities. [4][5][6][7][8][9] Recent studies have shown that curcumin also suppresses neuropathic pain induced by chronic sciatic nerve ligation.…”