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Mining Natural Product-Derived Molecules Against Cancer Targets: The Case of the Androgen Receptor in Prostate Cancer

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Alternative and Complementary Therapies for Cancer

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Abstract

Androgen receptor (AR) signaling is critical for prostate cancer progression. This has provided the rationale for the use of androgen ablation therapy, involving either surgical or chemical castration, to reduce androgen production and antiandrogen agents to antagonize androgen activity. Flutamide, nilutamide, and bicalutamide represent the main nonsteroidal antiandrogens currently used in practice. However, their efficacy is limited by progression of prostate cancer from hormone-responsive to hormone-refractory phenotype, where cancer cells become resistant to androgen ablation therapy. The most common treatment for hormone-refractory prostate cancer (HRPC) include docetaxel-based chemotherapy, which can lead to a modest improvement in the overall survival, underscoring the urgent need for novel therapeutics for advanced prostate cancer. As the vast majority of HRPC cells overexpress AR and remain dependent on AR signaling, there are considerable ongoing efforts to identify novel AR antagonists. Several novel antiandrogens, including MDV-3100, BMS–641988 and VN/124-1, and CYP17a inhibitors such as abiraterone acetates, are under clinical trials for the management of HRPC. In this chapter, we have reviewed the current state of the development of AR antagonists, with emphasis on those derived from herbal medicinal products, including from Chinese traditional medicine. The current progress in building chemical databases of natural products has provided opportunities for mining natural products against AR by using integrative in silico tools. Reinforcement of this trend will lead to discovery of novel natural product-derived antiandrogens with effectiveness against HRPC.

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Abbreviations

AR:

Androgen receptor

CML:

Chronic myelogenous leukemia

CYP17:

17α-hydroxylase/C17,20-lyase

DBD:

DNA-binding domain

DHT:

Dihydro-testosterone

3D:

Three-dimensional

H12:

Helix-12

HRPC:

Hormone-refractory prostate cancer

LBD:

Ligand-binding domain

NTD:

N-terminal domain

PSA:

Prostate-specific antigen

QCAR:

Quantitative-composition-activity relationship

TCM:

Traditional Chinese medicine

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Authors and Affiliations

  1. Department of Oncology, Segal Cancer Center, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, QC, Canada

    Jian Hui Wu

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  1. McGill University, Department of Medicine and Oncology,, Faculty of Medicine, Montreal, H3T 1E2, Canada

    Moulay Alaoui-Jamali

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Wu, J.H. (2010). Mining Natural Product-Derived Molecules Against Cancer Targets: The Case of the Androgen Receptor in Prostate Cancer. In: Alaoui-Jamali, M. (eds) Alternative and Complementary Therapies for Cancer. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-0020-3_26

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