Novel Targeted Pro-Apoptotic Agents for the Treatment of Prostate Cancer

Purpose

We reviewed and highlighted novel targeted apoptotic mediated therapies that can be used to treat prostate cancer.

Materials and Methods

A comprehensive review of the peer reviewed literature in the area of apoptosis was performed with special emphasis on apoptotic mediated pathways with promising novel targeted therapies that can be used for patients with prostate cancer.

Results

The apoptotic pathway can be classified into 2 separate broad categories, including the extrinsic and the intrinsic pathways. Targeting the extrinsic or intrinsic mediated pathway holds promise for developing novel agents for treating prostate cancer. We discuss apoptosis related molecules and therapies, as categorized by 1) targeting apoptosis pathway for antitumor treatment, 2) targeting apoptosis regulators for antitumor treatment and 3) drugs that potentiate pro-apoptotic agents.

Conclusions

Defining the molecules responsible for apoptosis and their intricate molecular interactions will help guide us in developing drugs with less toxicity for appropriately selected patients with prostate cancer and other malignancies. Because neoadjuvant and adjuvant clinical trials are under way using novel pro-apoptotic agents for prostate cancer, it is imperative for urologists to be active members of the clinical research team and become familiar with the molecular pathways, and potential benefits and toxicities associated with these novel agents.

Key Words: prostate, prostatic neoplasms, apoptosis, drug therapy, apoptosis regulatory proteins

Abbreviations and Acronyms: AIPC, androgen independent prostate cancer, BIR, baculovirus IAP repeat, CDDO, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid, c-FLIP, cellular FLICE-inhibitory protein, c-FLIP(L), c-FLIP (long), COX-2, cyclooxygenase-2, DISC, death-inducing signaling complex, DR, death receptor, FADD, Fas associated protein with death domain, HDAC, histone deacetylase, HDACI, HDAC inhibitor, IAP, inhibitor of apoptosis proteins, IκB, inhibitor of NF-κB, IKK, IκB kinase, IMiD, immunomodulatory drug, mTOR, mammalian target of rapamycin, NF-κB, nuclear factor-κB, OPG, osteoprotegerin, PI3K, phosphatidylinositol 3-kinase, PSA, prostate specific antigen, PTEN, phosphatase and tensin homolog deleted on chromosome ten, Smac, second mitochondria-derived activator of caspases, TNF, tumor necrosis factor, TRAF, TNF receptor-associated factor, TRAIL, TNF-related apoptosis-inducing ligand