curcumin and afimoxifene

Triple negative breast cancer (TNBC) is the hardest breast cancer subtype to treat due to lacking therapeutic target and treatment options. In this study, we found that SLUG expression was much higher in TNBC MDA-MB-231 cells than estrogen receptor alpha (ERα) positive breast cancer MCF7 cells. 4-hydroxytamoxifen (4-OHT) promoted SLUG expression, which was blocked by curcumin. Further investigation showed that SLUG activated the transcription of hexokinase-2 (HK2) by binding to HK2 promoter. SLUG knockdown inhibited HK2 expression and weakened 4-OHT resistance of MDA-MB-231 cells. Conversely, SLUG overexpression elevated HK2 level and increased 4-OHT resistance of MCF7 cells. Combination of curcumin and 4-OHT suppressed SLUG and HK2 expression, leading to mitochondrion-mediated apoptosis. These results suggested SLUG as a potential target and curcumin as a promising natural agent for overcoming 4-OHT resistance of TNBC.

Topics: Antineoplastic Agents; Apoptosis; Base Sequence; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromatin Immunoprecipitation; Curcumin; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Flow Cytometry; Glycolysis; Hexokinase; Humans; Mitochondria; Molecular Sequence Data; Promoter Regions, Genetic; Snail Family Transcription Factors; Tamoxifen; Transcription Factors; Triple Negative Breast Neoplasms

The effects of curcumin, a natural anti-cancer compound, on the bioavailability and pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, were investigated in rats. Tamoxifen and curcumin interact with cytochrom P450 (CYP) enzymes and P-glycoprotein, and the increase in the use of health supplements may result in curcumin being taken concomitantly with tamoxifen as a combination therapy to treat or prevent cancer. A single dose of tamoxifen was administered orally (9 mg x kg(-1)) with or without curcumin (0.5, 2.5 and 10 mg x kg(-1)) and intravenously (2mg x kg(-1)) with or without curcumin (2.5 and 10 mg x kg(-1)) to rats. The effects of curcumin on P-glycoprotein (P-gp) and CYP3A4 activity were also evaluated. Curcumin inhibited CYP3A4 activity with 50% inhibition concentration (IC50) values of 2.7 microM. In addition, curcumin significantly (P < 0.01 at 10 microM) enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp in a concentration-dependent manner. This result suggested that curcumin significantly inhibited P-gp activity. Compared to the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve (AUC(0-infinity)) and the peak plasma concentration (C(max)) of tamoxifen were significantly (P < 0.05 for 2.5 mg x kg(-1); P < 0.01 for 10 mg x kg(-1)) increased by 33.1-64.0% and 38.9-70.6%, respectively, by curcumin. Consequently, the absolute bioavailability of tamoxifen in the presence of curcumin (2.5 and 10 mg x kg(-1)) was 27.2-33.5%, which was significantly enhanced (P < 0.05 for 2.5 mg x kg(-1); P < 0.01 for 10 mg x kg(-1)) compared to that in the oral control group (20.4%). Moreover, the relative bioavailability of tamoxifen was 1.12- to 1.64-fold greater than that in the control group. Furthermore, concurrent use of curcumin significantly decreased (P < 0.05 for 10 mg x kg(-1)) the metabolite-parent AUC ratio (MR), implying that curcumin may inhibit the CYP-mediated metabolism of tamoxifen to its active metabolite, 4-hydroxytamoxifen. The enhanced bioavailability of tamoxifen by curcumin may be mainly due to inhibition of the CYP3A4-mediated metabolism of tamoxifen in the small intestine and/or in the liver and to inhibition of the P-gp efflux transporter in the small intestine rather than to reduction of renal elimination of tamoxifen, suggesting that curcumin may reduce the first-pass metabolism of tamoxifen in the small intestine and/or in the liver by i

Topics: Administration, Oral; Animals; Antineoplastic Agents, Hormonal; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cell Line, Tumor; Chromatography, High Pressure Liquid; Curcumin; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Erythromycin Ethylsuccinate; Fluorescent Dyes; Humans; Indicators and Reagents; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Rhodamine 123; Tamoxifen