The present proposal for preclinical studies with 12-O-tetradecanoylphorbol-13-acetate (TPA) will: 1. Identify and characterize combinations of TPA and other potential therapeutic agents that may enhance differentiation and therapeutic efficacy and overcome potential resistance to TPA-induced differentiation in the treatment of myeloid malignancies. 2. Examine the hypothesis that the effects of TPA, all-trans retinoic acid (ATRA), 1 alpha,25-dihydroxyvitamin D3 or butyrate alone or as synergistic combinations are mediated through changes in the levels and translocation of PKC alpha, PKC beta and PKC delta, and on the expression of mRNAs for PKC alpha, PKC beta and PKC delta in TPA-sensitive HL-60 and TPA-resistant HL-525 cells. We will also determine the effects of selective inhibitors of PKC beta and PKC delta as well as the expression of dominant negative PKC isoforms in HL-60 cells on the differentiation response of these cells to TPA alone or together with potential synergistic agents. The effects of overexpression of constitutive PKC isoforms on the action of TPA alone to cause differentiation in TPA-resistant HL-525 cells will also be determined. 3. Study the hypothesis that TPA may have therapeutic efficacy for inducing cytotoxicity in human prostate cancer cells. Specifically, we will determine the effects of TPA alone or in combination with (a) differentiating agents (ATRA, 1alpha, 25-dihydroxyvitamin D3, and butyrate), (b) inhibitors of NF-kappaB (BAY 11-7082) or (c) cytotoxic drugs (taxol, taxotere, mitoxantrone and estramustine) on proliferation and apoptosis of cultured human prostate cancer cell lines. We will test the hypothesis that levels of constitutive NF-kappaB activity determine sensitivity of these cells to TPA-induced cytotoxicity. The effects of TPA alone or in combination with synergizers on the levels and translocation of PKC alpha PKC beta and PKC delta and on the expression of these genes in prostate cancer cells will be evaluated. 4. Determine the in vivo effects of TPA alone, or in combination with other agents that are synergistic, on the growth of human prostate tumors in immunodeficient mice. Blood levels of TPA that are associated with inhibition of tumor growth will be determined. The effect of inhibitors of tumor growth on proliferation and apoptosis in the tumors will be determined.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092268-03
Application #
6940754
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
2003-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$276,790
Indirect Cost
Name
Rutgers University
Department
Biology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan et al. (2008) Inhibitory effect of voluntary running wheel exercise on the growth of human pancreatic Panc-1 and prostate PC-3 xenograft tumors in immunodeficient mice. Oncol Rep 19:1583-8
Zheng, Xi; Chang, Richard L; Cui, Xiao-Xing et al. (2008) Inhibition of NF-kappaB by (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY11-7082;BAY) is associated with enhanced 12-O-tetradecanoylphorbol-13-acetate-induced growth suppression and apoptosis in human prostate cancer PC-3 cells. Int J Oncol 32:257-64
Zheng, Xi; Cui, Xiao-Xing; Avila, Gina E et al. (2007) Atorvastatin and celecoxib inhibit prostate PC-3 tumors in immunodeficient mice. Clin Cancer Res 13:5480-7
Zheng, Xi; Chang, Richard L; Cui, Xiao-Xing et al. (2006) Effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with paclitaxel (Taxol) on prostate Cancer LNCaP cells cultured in vitro or grown as xenograft tumors in immunodeficient mice. Clin Cancer Res 12:3444-51
Hansson, Annette; Marin, Yari E; Suh, Junghan et al. (2005) Enhancement of TPA-induced growth inhibition and apoptosis in myeloid leukemia cells by BAY 11-7082, an NF-kappaB inhibitor. Int J Oncol 27:941-8
Zheng, Xi; Ryan, Amanda; Patel, Namrata et al. (2005) Synergistic stimulatory effect of 12-O-tetradecanoylphorbol-13-acetate and capsaicin on macrophage differentiation in HL-60 and HL-525 human myeloid leukemia cells. Int J Oncol 26:441-8
Avila, Gina E; Zheng, Xi; Cui, Xiao Xing et al. (2005) Inhibitory effects of 12-O-tetradecanoylphorbol-13-acetate alone or in combination with all-trans retinoic acid on the growth of cultured human pancreas cancer cells and pancreas tumor xenografts in immunodeficient mice. J Pharmacol Exp Ther 315:170-87
Zheng, Xi; Chang, Richard L; Cui, Xiao-Xing et al. (2004) Inhibitory effect of 12-O-tetradecanoylphorbol-13-acetate alone or in combination with all-trans-retinoic acid on the growth of LNCaP prostate tumors in immunodeficient mice. Cancer Res 64:1811-20