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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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Molecularly targeted radiosensitization of human prostate cancer by modulating inhibitor of apoptosis

Yao Dai1, Meilan Liu, Wenhua Tang

  • 1Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0582, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|December 3, 2008
PubMed
Abstract

Insights

Small-molecule inhibitor SH-130 enhances radiation therapy for prostate cancer by overcoming resistance. This approach sensitizes cancer cells to radiation, leading to significant tumor regression in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • Inhibitor of apoptosis proteins (IAPs) are overexpressed in hormone-refractory prostate cancer, contributing to radiation resistance.
  • Androgen-independent prostate cancer exhibits resistance to conventional radiation therapy.

Purpose of the Study:

  • To investigate the radiosensitizing effect of the small-molecule IAP inhibitor SH-130 in androgen-independent prostate cancer.
  • To elucidate the underlying mechanisms of radiosensitization induced by SH-130.

Main Methods:

  • Clonogenic survival assays and apoptosis assays were used to evaluate radiosensitization in DU-145 cells.
  • Pull-down and immunoprecipitation assays assessed the interaction between SH-130 and IAPs.
  • In vivo studies utilized DU-145 xenografts in nude mice to determine tumor suppression effects and toxicity.

Main Results:

  • SH-130 significantly enhanced radiation-induced apoptosis in DU-145 cells by interacting with X-linked IAP and cIAP-1.
  • In vivo, SH-130 sensitized DU-145 tumors to X-ray radiation, achieving over 80% complete tumor regression without systemic toxicity.
  • SH-130 partially inhibited nuclear factor-kappaB activation induced by TNF-alpha and radiation.

Conclusions:

  • Small-molecule IAP inhibitors can overcome apoptosis resistance and radiosensitize prostate cancer with high IAP levels.
  • Targeting IAPs with small molecules offers a promising strategy to improve outcomes in prostate cancer radiotherapy.

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