Potential Improvements on Therapy for Prostate Cancer

Nowadays, an increasing number of men are diagnosed with prostate cancer. Luckily, researchers from the Vancouver Prostate Centre have found two developed small drug compounds—VPC-14449 and VPC-14228, which can inhibit the activation level of the androgen receptor (AR) that promotes the appearance of prostate cancer (PCa) by targeting the DNA-binding domain (DBD) instead of the ligand-binding domain (LBD). Androgens activate AR when they bind to its LBD, allowing it to enter the nucleus and interact with other genes (Cutress et al., 2010).

Previous studies have used various treatments, including reducing the amount of androgens to inactivate the AR and using certain compounds to disassociate both genes and AR-LBD, thereby making LBD functionless and preventing binding to AR (Kush et al., 2014). However, these treatments can only inhibit the early stage of PCa and not the relapse and malignant conditions. Some findings indicated that the treatment compounds were ineffective in curing PCa after several variations on AR, such as different levels of splicing on LBD, which led treatment molecules to bind and inhibit AR inefficiently. Recently, a new treatment approach was found, and researchers recognized that certain therapy molecules were able to select and bind to the exposed areas of AR-DBD for reducing the activation level of AR (Kush et al., 2014).

Furthermore, scientists discovered two developed AR inhibitors, VPC-14228 and VPC-14449, and compared them with the well-known AR inhibitors pyrvinium and enzalutamide. As the findings show, pyrvinium was able to inhibit any form of AR, such as full-length and splicing, by selecting the exposure pocket on AR-DBD (Lim et al., 2014). Additionally, both VPC-14449 and enzalutamide were effective in inhibiting the same activation levels of AR by targeting the DBD. However, there are some differences presented. Pyrvinium caused a large number of cells to die when it was treated on AR, which made the conditions even worse. In contrast, both VPC-14449 and VPC-14228 were safe to use because of less toxicity. Following this finding, scientists made observations on different transcription receptors such as AR, ER, PR, and GR and then compared the differences in their activation levels by adding these two developed AR inhibitors (as shown in the figure below).

The figure above demonstrates the effect of the four different transcription receptors' activation levels by targeting different concentrations of enzalutamide, VPC-14228, and VPC-14449 on their own DBD. The control of this experiment should be figure 2-A, which is adding different concentrations of enzalutamide to AR, ER, GR, and PR. We chose figure 2-A as the control because it shows people how the original activation percentage of these four transcription receptors looks like and then compares it with the conditions of targeting two developed anti-androgen compounds on DBD. From both figure 2-B and C, VPC-14228 and VPC-14449 inhibit the activation level of ER when concentrations are higher than 5 µM. Different from this, the control figure shows that the full-length of AR is well inhibited by enzalutamide at its variety level of concentrations compared with the other two. Moreover, these three compounds are all inhibiting both GR and PR, even at 25 µM. The reason for showing such a phenomenon may be due to the lack of DNA-binding domain, which causes all three anti-androgen compounds to fail to bind to DBD and then maintain the activation of GR and PR. Comparing the activation level of AR in figure 2-A and C, the same trend of well inhibitions by targeting enzalutamide and VPC-14449 on AR-DBD has been shown, which also proves the discussions in the previous paragraph. Additionally, VPC-14228 does not inhibit AR as strongly as the other two compounds at their high concentration levels, which suggests that VPC-14449 has a better success rate in inhibiting the activation level of AR and reducing the size of tumors, and thus a better chance to treat prostate cancer.

In conclusion, researchers have developed better therapies to inhibit prostate cancer due to its universality. They replaced the treatment of binding anti-androgen compounds to LBD with targeting DBD due to frequent mutations in LBD. Additionally, scientists also noticed that several well-known treatment compounds were closely related to apoptosis, such as pyrvinium. Because of that, two anti-androgen compounds have been developed, which are VPC-14228 and VPC-14449, to better inhibit AR and reduce the size of tumors by closely associating with chromatin within the body cells. Moreover, figure 2 proves that VPC-14449 can inhibit the activation level of AR slightly better than VPC-14228. Finally, the study helps people who suffer from prostate cancer and suggests that further studies should be done to find more treatments.