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Vitamin E D-Tocotrienol Augments the Antitumor Activity of Gemcitabine and Suppresses Constitutive NF-Kb Activation in Pancreatic Cancer

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Vitamin E D-Tocotrienol Augments the Antitumor Activity of Gemcitabine and Suppresses Constitutive NF-Kb Activation in Pancreatic Cancer Published OnlineFirst October 4, 2011; DOI: 10.1158/1535-7163.MCT-11-0424 Molecular Cancer Preclinical Development Therapeutics Vitamin E d-Tocotrienol Augments the Antitumor Activity of Gemcitabine and Suppresses Constitutive NF-kB Activation in Pancreatic Cancer Kazim Husain1, Rony A. Francois1, Teruo Yamauchi1, Marta Perez1, Said M. Sebti2, and Mokenge P. Malafa1,2 Abstract The NF-kB transcription factor functions as a crucial regulator of cell survival and chemoresistance in pancreatic cancer. Recent studies suggest that tocotrienols, which are the unsaturated forms of vitamin E, are a promising class of anticancer compounds that inhibit the growth and survival of many cancer cells, including pancreatic cancer. Here, we show that tocotrienols inhibited NF-kB activity and the survival of human pancreatic cancer cells in vitro and in vivo. Importantly, we found the bioactivity of the four natural tocotrienol compounds (a-, b-, d-, and g-tocotrienol) to be directly related to their ability to suppress NF-kB activity in vitro and in vivo. The most bioactive tocotrienol for pancreatic cancer, d-tocotrienol, significantly enhanced the efficacy of gemcitabine to inhibit pancreatic cancer growth and survival in vitro and in vivo. Moreover, we found that d-tocotrienol augmentation of gemcitabine activity in pancreatic cancer cells and tumors is associated with significant suppression of NF-kB activity and the expression of NF-kB transcriptional targets (Bcl-XL, X-linked inhibitor of apoptosis, and survivin). Our study represents the first comprehensive preclinical evaluation of the activity of natural vitamin E compounds in pancreatic cancer. Given these results, we are conducting a phase I trial of d-tocotrienol in patients with pancreatic cancer using pancreatic tumor cell survival and NF-kB signaling components as intermediate biomarkers. Our data also support future clinical investigation of d-tocotrienol to augment gemcitabine activity in pancreatic cancer. Mol Cancer Ther; 10(12); 2363–72. Ó2011 AACR. Introduction pancreatic cancer (11–14). However, translation of these studies to the clinic has been challenging due to the low Pancreatic cancer is a leading cause of cancer mortality bioavailability of some of these natural compounds in with less than 5% of patients surviving 5 years after humans. diagnosis (1). Gemcitabine is a mainstay treatment for Tocotrienols, a group of 4 (a-, b-, d-, and g-tocotrienol) pancreatic cancer (2). However, tumor resistance to gem- unsaturated naturally occurring vitamin E compounds citabine therapy is common, making this a critical chal- (Fig. 1A), have received increasing attention for their lenge for pancreatic cancer management. potential as nontoxic dietary anticancer agents (15, 16). Prosurvival signaling mediated by the transcription Our group recently showed that oral administration of factor NF-kB is a key player in gemcitabine resistance in 100 mg/kg/d of d-tocotrienol to mice resulted in levels pancreatic cancer (3–11). Therefore, targeting dysregu- that were 10 times higher in pancreas than in subcutane- lated NF-kB signaling is an important strategy to improve ously implanted tumor tissue, suggesting that these com- the efficacy of gemcitabine therapy and thereby improve pounds will have reasonable bioavailability for pancreatic outcomes for patients with pancreatic cancer. Several tumor intervention (17). In this study, we investigated the studies have combined natural compounds that inhibit potential of the 4 natural tocotrienols to inhibit pancreatic NF-kB, such as genistein, curcumin, fisetin, and green tea, cancer and NF-kB activation in vitro and in vivo. In addi- with gemcitabine to investigate synergy in treating tion, we investigated the potential of the most bioactive tocotrienol to augment gemcitabine activity in vitro and in vivo. Authors' Affiliations: Departments of 1Gastrointestinal Oncology and 2Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida Materials and Methods Corresponding Author: Mokenge P. Malafa. Department of Gastrointes- tinal Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL Chemicals and cell lines 33612. Phone: 813-745-1432; Fax: 813-745-7229; E-mail: All chemicals and reagents were purchased from Sigma- fi mokenge.malafa@mof tt.org Aldrich unless otherwise specified. Tocotrienols (a, b, g, doi: 10.1158/1535-7163.MCT-11-0424 and d)anda-andd-tocopherol were obtained from Davos Ó2011 American Association for Cancer Research. Life Ltd. Gemcitabine-HCl was purchased from Eli Lilly www.aacrjournals.org 2363 Downloaded from mct.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst October 4, 2011; DOI: 10.1158/1535-7163.MCT-11-0424 Husain et al. CH3 140 ABHO AsPc-1 MiaPaCa-2 CH3 CH3 CH3 CH3 120 CH 3 O CH3 100 CH α # 3 -Tocotrienol # CH 80 # # 3 # * * * # HO # * * CH CH CH 60 * * 3 3 3 * * * * CH3 * * * * * * * O CH3 40 * * * % cell viability CH β * * 3 -Tocotrienol 20 * * HO CH CH CH 0 CH 3 3 3 3 icle mol/L mol/L mol/L mol/L mol/L mol/L mol/L mol/L eh mol/L mol/L mol/L mol/L mol/L mol/L mol/L CH O CH μ μ μ V μ 3 3 0 10 20 μ 40 μ 50 μ 60 80 μ 10 μ 20 μ 40 μ 50 60 μ 80 μ γ 100 μ 100 μ CH3 -Tocotrienol 140 HPDE6 C7 HPDE6 C7-Kras HO 120 CH3 CH3 CH3 CH3 100 CH # O 3 # * CH δ-Tocotrienol 80 * 3 * 60 * * CH3 * * * HO 40 * CH3 CH3 CH3 % cell viability CH3 20 * CH3 O CH3 * 0 CH3 α-Tocopherol mol/L mol/L μmol/Lμmol/L mol/L mol/Lμmol/L mol/L μmol/L mol/L mol/L mol/L μmol/L mol/L mol/L mol/L 0 μ 0 10 μ 20 40 50 μ 60 μ 80 10 μ 20 μ 40 μ 50 60 μ 80 μ C 100 μ 100 μ Caspase-8 activity Caspase-3 activity α-Tocotrienol β-Tocotrienol γ-Tocotrienol δ-Tocotrienol α-Tocopherol 160 180 ** 140 * * 160 ** * 120 140 D 100 120 80 100 80 60 60 700 * P < 0.001 vs. vehicle 40 P 40 ** < 0.02 vs. vehicle 20 600 *** P < 0.05 vs. vehicle 20 # P < 0.02 vs. γ-T3 0 0 500 *** Caspase-8 activity (%) V α-T3 β-T3 γ -T3 δ-T3 α-T Caspase-3 activity (%) V α-T3 β-T3 γ -T3 δ-T3 α-T 400 ** α β Cell death ELISA Vehicle -T3 -T3 300 14 V α-T3 β-T3 γ-T3 δ-T3 200 *,# 12 No. of colonies PARP1 100 10 cleaved 8 0 Vehicle α-T3 β-T3 γ-T3 δ-T3 α-T 6 Bax 4 β-Actin γ-T3 δ-T3 α-T 2 0 MiaPaCa-2 cells 10-fold increase in apoptosis α-T3 β-T3 γ-T3 δ-T3 α-T Figure 1. A, chemical structures of tocotrienols and tocopherol. B, effect of tocotrienols on pancreatic cancer cell proliferation (MTT assay). Points, means; bars, SE (n ¼ 3–5; Ã, P < 0.001; #, P < 0.01). C, effect of tocotrienols on caspase-3 and 8 activities in MiaPaCa-2 cells (top left and right). Bars, SE (n ¼ 3; Ã, P < 0.05; ÃÃ, P < 0.01). Bottom left, effect of tocotrienols on pancreatic cancer apoptotic cell death (ELISA) in MiaPaCa-2 cells (n ¼ 3). Bottom right, Western blot analysis of PARP-1 cleavage and proapoptotic Bax protein expression in MiaPaCa-2 cells (n ¼ 3). D, effect of tocotrienols on pancreatic cancer malignant transformation assay in MiaPaCa-2 cells. d-Tocotrienol significantly inhibited malignant transformation compared with vehicle (Ã, P < 0.001) and b-or g-tocotrienol treatment (#, P < 0.02). In contrast, no effect was observed with a-tocotrienol or a-tocopherol treatment. Bars, SE (n ¼ 3). V, vehicle. and Company. L-Glutamine, penicillin, streptomycin, and tary extract. MiaPaCa-2 and AsPc-1 cells were grown in HEPES buffer were purchased from Mediatech. FBS was monolayers with DMEM and RPMI media, respectively, purchased from HyClone. Dulbecco’s Modified Eagle’s supplemented with 10% FBS, 2 mmol/L L-glutamine, Medium (DMEM), RPMI-1640, keratinocyte serum-free penicillin (50 IU/mL), and streptomycin (50 mg/mL). À medium, sodium pyruvate, trypsin-EDTA, and PBS were RPMI medium was also supplemented with 10 2 mol/L À purchased from Invitrogen. Ethanol (100%) was purchased HEPES buffer and 10 3 mol/L sodium pyruvate. Cells from Aaper Alcohol and Chemical. Pancreatic cancer cell were cultured at 37C in a humidified atmosphere of 5% lines MiaPaCa-2 and AsPc-1 were obtained from American CO2 and 95% O2. Type Culture Collection (ATCC). Human pancreatic ductal epithelial cells (HPDE6 C7) and HPDE6 C7-KRas cells were Cell proliferation MTT assay gifts from Dr. Tsao, Ontario Cancer Institute, University of Cells were seeded in 96-well plates at a density of 3,000 Toronto, Toronto, Ontario, Canada. These cells were cells per well and allowed to attach overnight. Cells were authenticated by morphologic, cell proliferation, and Myco- then incubated for 72 hours with various concentrations of À À plasma tests, as recommended in ATCC Technical Bulletin a-, b-, g-, and d-tocotrienol and a-tocopherol (10 5 to 10 4 No. 8 (2007). mol/L). In other experiments, cells were incubated for À À 72 hours with gemcitabine and d-tocotrienol (10 5 to 10 4 Cell culture and growth mol/L) and their combination or ethanol (<5%) in PBS as HPDE6 C7 and HPDE6 C7-KRas cells were grown in vehicle control. Media were aspirated and replaced with keratinocyte growth media (Invitrogen) supplemented 20 mL of 1 mg/mL MTT and incubated for 2 to 4 hours at with human epidermal growth factor and bovine pitui- 37 C in a humidified atmosphere of 5% CO2. Media were 2364 Mol Cancer Ther; 10(12) December 2011 Molecular Cancer Therapeutics Downloaded from mct.aacrjournals.org on September 23, 2021.
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