[Frontiers in Bioscience 11, 1549-1568, May 1, 2006]

APO2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in prostate cancer therapy

Octavian Bucur 1,3, Subrata Ray 1, Maria Cristina Bucur 3, and Alexandru Almasan 1,2

1Department of Cancer Biology, Lerner Research Institute, 2Department of Radiation Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA, 3 Department of Cellular and Molecular Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Receptors that bind Apo2L/TRAIL
2.2. Apoptosis activation: Apo2L/TRAIL as a critical trigger of the extrinsic apoptosis pathway
3. Apo2L/TRAIL-induced apoptosis in prostate cells
3.1. Role of Bcl-2 family members
3.2.. Role of NF-kappaB
3.3. Other forms of cell death
4. Prostate cancer cell models for determining sensitivity to Apo2L/TRAIL-induced apoptosis
4.1. Apo2L/TRAIL variants
4.2. Cell lines
4.3. Preclinical models
5. The mechanisms of resistance of prostate cancer cells to Apo2L/TRAIL
5.1. Bcl-2 and Inhibitors of Apoptosis Proteins
5.2. Survival factors
5.3. Androgen dependence
5.4. Other factors
6. Sensitization of prostate cancer cells to Apo2L/TRAIL-induced apoptosis
6.1. Conventional radiation and chemotherapeutic drugs
6.1.1. Anthracyclines: doxorubicin
6.1.2. Anthracenediones: actinomycin D
6.1.3. Pyrimidine analogs: 5-fluorouracil, gemcitabine
6.1.4. Platinum antitumor compounds: cisplatin
6.1.5. Taxanes: paclitaxel
6.1.6. Vinca alkaloids: vinblastine and vincristine.
6.1.7. Other chemotherapeutic agents
6.1.8. X-rays
6.2. Compounds that act on Bcl-2 family proteins
6.3. Inhibitors of cell survival factors
6.4. Histone deacetylase inhibitors
6.5. Metabolic inhibitors: blocking protein synthesis
6.6. Other types of treatment
6.7. Sensitization to Apo2L/TRAIL-induced apoptosis in vivo
7. Perspectives
8. Acknowledgments
9. References

1. ABSTRACT

Prostate cancer is one of the most common cancers in men and is the second leading cause of cancer-related death in the USA. Many anti-tumor agents against prostate cancer cells have been developed, but their unacceptable systemic toxicity to normal tissues usually limits their use in the clinic. Apo2 ligand (Apo2L), also called Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), is one of several members of the TNF gene superfamily that induces apoptosis through engagement of death receptors. This protein has generated tremendous enthusiasm as a potential tumor-specific cancer therapeutic because, as a stable trimer, it selectively induces apoptosis in many transformed cells, but not in most normal cells. In this review we discuss its potential use in prostate cancer therapy, the mechanisms by which induces apoptosis or that underlie resistance to it, and strategies for sensitization to overcome them. Conventional chemotherapeutic and chemopreventive drugs, irradiation, and other therapeutic agents, such as histone deacetylase inhibitors or retinoids can sensitize Apo2L/TRAIL-resistant cells and tumors. Investigating the apoptotic effects of Apo2L/TRAIL, a unique tumor-specific cell death ligand, now in clinical trials, alone or in combination may not only help in understanding its antineoplastic role in prostate carcinoma but may also provide insights into basic mechanisms of apoptosis.