Synergistic inhibition of tumor growth and metastasis by combined treatment with TNP-470 and docetaxel in a human prostate cancer PC-3 model

  • Authors:
    • Mototsugu Muramaki
    • Hideaki Miyake
    • Isao Hara
    • Sadao Kamidono
  • View Affiliations

  • Published online on: March 1, 2005     https://doi.org/10.3892/ijo.26.3.623
  • Pages: 623-628
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Abstract

TNP-470, a potent inhibitor of angiogenesis, was reported to synergistically enhance the antitumor effects of cytotoxic agents. The objective of this study was to evaluate the effectiveness of combined treatment with TNP-470 and docetaxel both in vitro and in vivo using androgen-independent human prostate cancer PC-3 cells. The in vitro growth-inhibitory and apoptotic effects of docetaxel and/or TNP-470 on PC-3 cells were assessed using MTT and TUNEL assays. The combined effect of docetaxel and TNP-470 therapy after subcutaneous and orthotopic injection of PC-3 cells into athymic nude mice was evaluated. In vivo effects of this combined regimen on PC-3 tumors were analyzed by the TUNEL assay and immunohistochemical staining of CD31 to quantify microvessel density (MVD). Combined treatment with TNP-470 and docetaxel synergistically inhibited PC-3 cell growth in vitro through the enhanced induction of apoptotic cell death compared with treatment with either agent alone, a result explained, at least in part, by the down-regulation as well as phosphorylation of potential anti-apoptotic genes, Bcl-2 and Bcl-XL. Combined treatment with TNP-470 and docetaxel synergistically suppressed subcutaneous PC-3 tumor growth compared with treatment with either agent alone. Furthermore, this combined regimen significantly inhibited orthotopic PC-3 tumor growth and reduced the incidence of lymph node metastasis. Immunohistochemical analysis of the subcutaneous tumor after each treatment demonstrated that administration of docetaxel as well as TNP-470 significantly induced apoptotic cell death; in contrast, a significant reduction in MVD was observed only after TNP-470. These findings suggest that docetaxel and TNP-470 act synergistically to inhibit PC-3 tumor growth and metastasis, by enhancing apoptosis and suppressing angiogenesis.

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March 2005
Volume 26 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Muramaki, M., Miyake, H., Hara, I., & Kamidono, S. (2005). Synergistic inhibition of tumor growth and metastasis by combined treatment with TNP-470 and docetaxel in a human prostate cancer PC-3 model. International Journal of Oncology, 26, 623-628. https://doi.org/10.3892/ijo.26.3.623
MLA
Muramaki, M., Miyake, H., Hara, I., Kamidono, S."Synergistic inhibition of tumor growth and metastasis by combined treatment with TNP-470 and docetaxel in a human prostate cancer PC-3 model". International Journal of Oncology 26.3 (2005): 623-628.
Chicago
Muramaki, M., Miyake, H., Hara, I., Kamidono, S."Synergistic inhibition of tumor growth and metastasis by combined treatment with TNP-470 and docetaxel in a human prostate cancer PC-3 model". International Journal of Oncology 26, no. 3 (2005): 623-628. https://doi.org/10.3892/ijo.26.3.623