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Piperine Enhances the Efficacy of TRAIL-Based Therapy for Triple-Negative Breast Cancer Cells

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Piperine Enhances the Efficacy of TRAIL-Based Therapy for Triple-Negative Breast Cancer Cells ANTICANCER RESEARCH 34: 1893-1900 (2014) Piperine Enhances the Efficacy of TRAIL-based Therapy for Triple-negative Breast Cancer Cells SHERIF ABDELHAMED1, SATORU YOKOYAMA1, ALAA REFAAT1, KEISUKE OGURA1, HIDEO YAGITA2, SURESH AWALE3 and IKUO SAIKI1 1Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Sugitani, Toyama, Japan; 2Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; 3Frontier Research Core for Life Sciences, University of Toyama, Sugitani, Toyama, Japan Abstract. Background/Aim: Triple-negative breast cancer While receptor-targeted therapeutics cannot help in the (TNBC) is most the aggressive type of breast cancer and is management of TNBC, tumor necrosis factor-related poorly responsive to endocrine therapeutics; however, one of apoptosis-inducing ligand (TRAIL) might be an attractive the most attractive treatments is tumor necrosis factor-related molecule against TNBC because of its high selectivity for apoptosis-inducing ligand (TRAIL)-based therapies. To various carcinoma over normal cells (3); however, primary identify compounds that enhance the efficacy of TRAIL-based or acquired resistance to TRAIL limits its clinical efficacy in therapies, we screened 55 compounds from natural products patients with cancer (4, 5). Several anti-apoptotic and pro- in combination with TRAIL in TNBC cells. Materials and survival molecules, including nuclear factor kappa-light- Methods: Human TNBC cells, MDA-MB-468 and MDA-MB- chain-enhancer of activated B cells (NF-κB), inhibitors of 231, and murine TNBC cells, 4T1, were used. Cell viability, apoptosis [such as X-linked inhibitor of apoptosis (XIAP) apoptotic cells, and cell cycle were quantified by the WST-1 and survivin] and B-cell lymphoma-2 (BCL2) family assay, annexin-V/7-amino-actinomycinD (7-AAD) staining members [such as myeloid leukemia cell differentiation and Propidium iodide (PI) staining, respectively. In vivo protein (MCL1)], are involved in acquired or hereditary effects of piperine were evaluated in the orthotopic-inoculated TRAIL-resistant mechanisms (6-11). 4T1-luc mouse model. Results: After screening, we identified In order to identify compounds that synergistically piperine as the most potent adjuvant at enhancing the efficacy enhance the efficacy of TRAIL-based therapy, we screened of TRAIL-based therapies in TNBC cells in vitro and in vivo, for 55 chemically-defined compounds isolated from natural which might be mediated through inhibition of survivin and products in TNBC cells. Among them, we identified piperine p65 phosphorylation. Conclusion: Piperine may enhance as a candidate, which has a potently enhancing effect on TRAIL-based therapeutics for TNBC. TRAIL-induced cytotoxicity in TRAIL-sensitive TNBC cells, MDA-MB-231, and also a sensitizing effect on TRAIL- Breast cancer is the most frequently-diagnosed type of resistant TNBC cells, MDA-MB-468. Piperine (Figure 1) is cancer among women and one of the main causes of cancer the major alkaloid isolated from Piper nigrum and Piper death (1, 2). Triple-negative breast cancer (TNBC), which is longum and exhibits a wide range of biological effects, estrogen receptor (ER)-negative, progesterone receptor (PR)- including anti-inflammatory and anti-arthritic effects (12). In negative, and epidermal growth factor receptor type 2 cancer, piperine inhibits angiogenesis (13) and the tumor (HER2)-negative, accounts for 15%-25% of all breast cancer necrosis factor-α (TNF-α)-induced activation of NF-κB (14). cases and is aggressive, poorly-prognosed, and unresponsive It is also known to enhance the effective bioavailability and to endocrine therapeutics. to inhibit the metabolism of major therapeutics by inhibiting cytochrome p450 enzymes (15, 16); however, there are no reports showing the potential effect of piperine in combination with TRAIL-based therapy. Correspondence to: Ikuo Saiki, Ph.D., Division of Pathogenic In the present study, we investigated the synergistic Biochemistry, Institute of Natural Medicine, University of Toyama, effects of piperine on TRAIL-induced apoptosis of TNBC 2630 Sugitani, Toyama 930-0194, Japan. Tel: +81 764347620, Fax: cells in vitro and in vivo. Collectively, aimed to +81 764345058, e-mail: [email protected] demonstrate that piperine, a commonly used dietary Key Words: Triple-negative breast cancer, piperine, TRAIL, ingredient, is effective in enhancing the TRAIL-based apoptosis. treatment of TNBC cells. 0250-7005/2014 $2.00+.40 1893 ANTICANCER RESEARCH 34: 1893-1900 (2014) approved (A2012INM-6) and performed according to the guidelines of the Care and Use of Laboratory Animals of University of Toyama. 4T1-luc murine cells were inoculated directly into the mouse mammary fat pad (1×105/mouse). The mice were anesthetized with Escain isoflurane (Mylan Seiyaku, Osaka, Japan). The substrate D- luciferin (150 mg/kg) was injected intraperitoneally. The mice were imaged by the IVIS lumina II system (Caliper Life Sciences, Figure 1. Structure of piperine. Hopkinton, MA, USA), and the bioluminescence signals were quantified by Living Image® software (Caliper Life Sciences). We performed imaging every 10 min up to 20 min to obtain the Materials and Methods maximum reading with 0.5-1 min exposure time. The primary tumor size was also measured using a caliper square along the longer axis (a) and shorter axis (b), and tumor volume was calculated by the Reagents. The compounds were isolated and purified at the Institute following formula: tumor volume (mm3)=ab2/2. of Natural Medicine, University of Toyama, Japan and were dissolved in dimethyl sulfoxide (DMSO). Recombinant human Statistical analysis. Data are presented as the mean±SEM of TRAIL was purchased from PeproTech (Peprotech, London, UK). experiments. Statistical significance for group comparisons was Agonistic monoclonal antibody to death receptor 5 (anti-DR5) was performed using two-way analysis of variance (ANOVA) with the prepared as described previously (17). Bonferroni post-tests and Student’s t-test for single comparisons. Cell culture. MDA-MB-231 and MDA-MB-468 human breast cancer cells [American Type Culture Collection (ATCC), Rockville, Results MD, USA] were cultured in Dulbecco’s modified Eagle’s medium, and 4T1 murine cells (ATCC) were cultured in RPMI-1640 medium. Piperine in combination with TRAIL suppresses cell growth All media were supplemented with 10% heat-inactivated fetal calf in both TRAIL-sensitive and TRAIL-resistant human TNBC serum, 2 mM L-glutamine, 100 units/ml penicillin, and 100 μg/ml streptomycin. Cells were maintained at 37˚C in a humidified cells. We screened 55 compounds derived from natural atmosphere of 5% CO2. products with or without TRAIL for cell growth in human TNBC cells, MDA-MB-231 and MDA-MB-468 cell lines, Cell viability assay. Cell viability was determined using the Cell TRAIL-sensitive and TRAIL-resistant cells, respectively (6). Counting Kit (Dojindo, Kumamoto, Japan), as described previously Upon screening, we found that alisol A, curcumin, and 3 (6). Briefly, cells were seeded into a 96-well plate (7×10 /80 μl/well). piperine showed a synergistic suppression of cell growth in Thirty minutes before TRAIL addition (50 ng/ml), 10 μl medium both TNBC cells (synergy index <0.8, Table I). Contrary to containing test compounds (final concentration 50 μM) was added. After 24 h incubation, cells were counted with the Cell Counting Kit. TRAIL, piperine treatment alone suppressed growth of Relative cell viability was calculated by the formula: Relative cell MDA-MB-468 but not of MDA-MB-231 cells; therefore, we viability=[average absorbance of experimental wells/average decided to further focus on piperine. absorbance of control wells]. The synergy index was calculated as To confirm the above screening results, both TNBC cell follows: viability with combination treatment/[viability with TRAIL lines were treated with different concentrations of piperine with alone with compound alone]. and without TRAIL (Figure 2a). Consistent with the screening Apoptosis assay. The cells were treated with piperine and TRAIL, results, piperine suppressed cell growth of MDA-MB-468 cells similar to the cell viability assay, and were subjected to the annexin- but not of MDA-MB-231 cells, and furthermore, piperine and V/Dead Cell-Kit using a Muse Cell Analyzer (Merck Millipore, TRAIL combination, synergistically inhibited cell growth of Hayward, CA, USA), as described in the manufacturer’s instructions. both cell lines compared to either treatment alone. We next determined whether the growth suppression of piperine and Cell-cycle analysis. After treatment with piperine (200 μM) for 8 h TRAIL combination is due to induction of the typical apoptotic and 24 h, the cells were collected, washed with cold phosphate- pathway using annexin-V and 7-Amino-Actinomycin D (7- buffered saline (PBS), fixed in cold 70% ethanol and stored at −20˚C overnight. The cells were then subjected to the Muse Cell- AAD) staining. Piperine treatment in combination with TRAIL Cycle Kit (Merck Millipore). significantly increased apoptotic cells compared to either treatment alone for both cell lines (Figure 2b). Similarly, Western blot analysis. Western blot analysis was performed as cleavage of caspase-3 and PARP, both of which are known previously described (6). Primary antibodies used were to: caspase- apoptotic markers, was clearly induced by piperine and TRAIL 3, poly ADP-ribose polymerase (PARP), survivin, XIAP, MCL1, B- combination in both cell lines (Figure 2c). Unlike growth cell lymphoma-extra large (BCL-xl) and phosphorylated p65 from suppression, piperine treatment did not induce apoptosis of Cell Signaling Technology (Danvers, MA, USA); and β-Actin and p65 from Santa Cruz Biotechnology (Santa Cruz, CA, USA). MDA-MB-468 cells. With regard to cell-cycle status, piperine treatment led to cell-cycle arrest at the G2/M phase in MDA- Animal model. BALB/c mice (6 weeks old, female) were purchased MB-468 cells but not in MDA-MB-231 cells (Figure 2d). from Japan SLC Inc. (Hamamatsu, Japan) All experiments were Collectively, the growth suppression of the piperine and TRAIL 1894 Abdelhamed et al: Piperine-enhanced Efficacy of TRAIL-based Therapy of TNBC Cells Figure 2.
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