Abstract
Treatment of cultured PANC-1, MIA PaCa-2, and BxPC-3 human pancreatic adenocarcinoma cells with 0.1 to 1.6 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 96 h inhibited the proliferation of these cells in a dose-dependent manner, and PANC-1 and MIA PaCa-2 cells were more sensitive to TPA than BxPC-3 cells. Inhibition of proliferation by TPA in PANC-1 cells was associated with an increase in the level of p21, but this was not observed in MIA PaCa-2 or BxPC-3 cells. The TPA-induced increase of p21 in PANC-1 cells was blocked by bisindolylmaleimide or rottlerin (inhibitors of protein kinase C). Studies in NCr-immunodeficient mice with well established PANC-1 tumor xenografts indicated that daily i.p. injections of TPA strongly inhibited tumor growth, increased the percentage of caspase-3-positive cells, and decreased the ratio of mitotic cells to caspase-3-positive cells in the tumors. Studies with BxPC-3 tumors in NCr mice receiving daily i.p. injections of vehicle, TPA, all-trans retinoic acid (ATRA), or a TPA/ATRA combination showed that TPA had an inhibitory effect on tumor growth, but treatment of the animals with the TPA/ATRA combination had a greater inhibitory effect on tumor growth than TPA alone. Treatment with the TPA/ATRA combination resulted in a substantially decreased ratio of the percentage of mitotic cells to the percentage of caspase-3-positive cells in the tumors compared with tumors from the vehicle-treated control animals. The inhibitory effects of TPA on tumor growth occurred at clinically achievable blood levels.
Footnotes
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This study was supported in part by National Institutes of Health Grant CA092268.
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doi:10.1124/jpet.105.087585.
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ABBREVIATIONS: TPA, 12-O-tetradecanoylphorbol-13-acetate; ATRA, all-trans retinoic acid; BAY 11-7082, (E)-3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; RIPA, radioimmunoprecipitation; PAGE, polyacrylamide gel electrophoresis; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PKC, protein kinase C; ANOVA, analysis of variance; NF-κB, nuclear factor-κB; STAT, signal transducer and activator of transcription; Rb, retinoblastoma; DMSO, dimethyl sulfoxide; Gö6976, 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole; Gö6983, 2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide; API-2, triciribine.
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↵1 Current address: Department of Medical Oncology and Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
- Received April 8, 2005.
- Accepted June 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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