As the most predominant cause of cancer-related death for men in the U.S., prostate cancer has been the subject of extensive research that has led to a better understanding of the disease and metastasis mechanism.

Since the increased levels of androgen or its signaling activities in males have been shown to be partially responsible for prostate cancer, decreasing the amount of androgens and/or its signaling pathway activity has been attempted. This can be achieved by either surgical or chemical castration as the main treatment.

Currently, chemical castration or androgen deprivation therapy (ADT) is among the most widely accepted and used treatment options, leading to a reduced prostate specific antigen (PSA). This, in turn, has been shown to limit the circulating tumor cells (CTC) count in the patients.

Androgen receptor signaling could be a major player in prostate cancer development and progression. Furthermore, ongoing research about androgen receptor regulation has led to production of different drugs that can directly or indirectly block the androgen receptor or interfere with its signaling pathway and lead to cancer regression.

Androgen receptor overexpression or mutation has been suggested to be the potential mechanism for castration-resistant prostate cancer (CRPC). There are a variety of mutations that could happen to allow androgen receptor pathway activation by other nonspecific ligands or cause a constitutively active androgen receptor.

To disrupt this cycle, many studies have focused on drugs that can inhibit the androgen receptor complex to prevent androgen receptor behavior as a transcription factor. The interruption of the androgen receptor complex could be confirmed by measuring the PSA level and observing it decreasing.

There are many drugs that directly target the androgen receptor. Enzalutamide (MDV 3100) is the most popular one, which is an androgen receptor antagonist that is administered orally. It targets several steps of androgen receptor signaling pathway. It has been proven effective in 50 percent of the cases by decreasing the PSA levels.

Enzalutamide is under first phase 3 trial, and the only side effect reported has been fatigue so far. However, there have been concerns regarding seizures that are under investigation.

ARN-509 is another drug in phase 2 trial that is more potent, so it can be used in lower doses to eliminate any potential side effects. Also, Bicalutamide is still under review.

Furthermore, there are drugs that indirectly target the androgen receptor. Ketoconazole is one of them, which is not commonly used with a wide range of side effects and not being a specific inhibitor. Abiraterone acetate, orteronel (TAK-700) and lupron are other drugs that are being researched.

Another category of drugs that are under investigation are the ones targeting heat-shock proteins. Heat-shock protein 90 (HSP90) regulates the function of many proteins, including the androgen receptor. Heat-shock protein inhibitors have shown promising results in prostate cancer treatment strategy.

Natural agents are yet another category of alternatives to treat prostate cancer. They have been shown to be more effective with fewer side effects. Selenium, soy, isoflavons, green tea are some examples of these natural agents that resulted in a decreased androgen receptor expression [10].

Furthermore, curcumin has been reported to act as an androgen receptor antagonist. BR-DIIM, which is the formulated version of 3,3’-diindolylmethene (DIM) and is found in cruciferous vegetables, has been shown to decrease the growth of prostate cancer.

In conclusion, further studies to elaborate on the mechanism of action and signaling pathway for prostate cancer and its progression could allow for a better understanding of the disease, which will then enable us to discover more effective treatment strategies for it.