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

Authors:
  • XZXi Zheng
    Xi Zheng
  • XCXiao Xing Cui
    Xiao Xing Cui
  • ARAmanda D. Ryan
    Amanda D. Ryan
  • AHAnnette Hansson
    Annette Hansson
  • JSJunghan Suh
    Junghan Suh
  • ARArnold B. Rabson
    Arnold B. Rabson
  • RCRichard L. Chang
    Richard L. Chang
  • WSWeichung Joe Shih
    Weichung Joe Shih
  • YLYong Lin
    Yong Lin
  • PCPamela Crowell
    Pamela Crowell
  • YLYao Ping Lu
    Yao Ping Lu
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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.

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