Prostate cancer is considered to be next in rank to the first reason of cancer throughout the whole globe. According to a research 29,000 men was predicted to be dead due to prostate cancer in 2014. It was found that testosterone suppression with hormone therapy paved a milestone in the treatment of patients who were having severe metastatic disease. The initial attempt to reduce the amount of testosterone and modifying the AR axis was believed to be a controlling factor for this disease. (Sternberg, Petrylak, Madan & Parker, 2014)
Being the second purpose of death prostate cancer is common mainly in male. The scopes of treatment for such cancer are ADT (Androgen deprivation therapy) or castrating surgically or chemically. Though these treatment options are highly effective but after some times CRPC is seen in the patients. Because of the CRPC implementations of other therapies have been made and androgen axis can be blocked. So, this has made the androgens and AR signaling pathway a very significant in prostate cancer advancement. In addition to their effects on the prostate tumor cells the ADTs show impact on the immune system too. (Gamat & McNeel, 2017)
For the treatment of repeated prostate cancer the ADTs are the basic options. The ADTs have systemic immunomodulatory effect and cases thymopoiesis. In the modern time the combination of ADTs with immunotherapy has been showing the ability to improve the output of prostate cancer immunotherapy. Clinical trials of such combination therapies are already being investigated but there remain some doubts on 1) the best androgen-targeted-agents, 2) best series of therapies and 3) the applicability of these combination therapies. It is expected that within the next 5-10 years we might be able to clarify these doubts and ultimately it will lead us to design a safer and sustainable treatment therapy of prostate cancer. (Gamat & McNeel, 2017)
The core objectives of this particular study on “Anti-androgen therapies in prostate cancer” are:
To have an insight of prostate cancer.
To understand how anti-androgen therapies are given.
To know the pharmacokinetics of anti-androgens.
To know about ongoing researches.
To know about few cases.
The androgen testosterone are the elementary agonists for the AR while the DHT( dihydrotestosterone) being the most useful one. These can attach on the AR-LBD and can cause a conformational change and as a result the foldsome can be moved to a new location and the AR can dislocate inside the nucleus. Then dimerization of the AR takes place and the AR interact with DNA androgen-responsive elements(AREs) and finally cell proliferation takes place. (cano et al., 2013). The additional transactivation of AR can be done through growth factors and cytokines. The sophisticated activity and biology of the AR is also related with AR signaling that is started from the MISS which are the binding sites and the plasma membrane being the location of the MISS. The MISS can be further explained in multiple cell lines, even the cells produced from prostate cancer and it is separable from the observable effects that are related to the NISS. According to Pelekanou et al. it is stated that “membrane androgen binding sites have been described in cell lines and prostate specimens, even in the absence of the full length receptor FL-AR.” (Pelekanou & Castanas, 2016)
Though there’s been a major improvement in the drug development of prostate cancer castration resistance disease in found in the majority of the cancer patients of prostate cancer. Firstly we need to understand what CPRC is. CPRC can be defined as a condition where the androgen signaling remains prominent by the cells and in addition to that they can evade cell death or apoptosis even under the ADT. In order to elucidate the disease condition such term CPRC is applied even if the testosterone level in the circulation persists in castration range (50 ng/dl, alternative to 280-1100 ng/dl which is considered as normal in males), on the other hand tumor growth remains at large due to the AR signaling. According to few researches the castration resistance can be done based few mechanisms such as, 1) AR and ligand dependency, 2) AR dependency and ligand independency, 3) AR and ligand independency. (Pelekanou ; Castanas, 2016)
The imprimatur of abiraterone and enzalutamide has been a break through event in the medication of advanced CRPC which in turn pushed the level of management of prostate cancer to a whole new level. And the advantages were found to be in the recoil of the disease, clinical profit, and better tolerance. Even though with this much huge advancement the ADT resistance is being a significant problem for the enzalutamide and abiramide. According to Narayanan et al,. a study from 2016 stated that, “nevertheless, these two drugs have provided strong evidence on the importance of AR targeting, even under castration resistance”. Abiraterone and enzalutamide both have been able to show elevated containment of this cancer and such facts obvious. These two drugs have been able to provide the mechanisms that refer to the AR axis, drug resistance improvements, tumor cell anointment even under the ADT. (Pelekanou ; Castanas, 2016) Among the other achievements that these two drugs have earned are:
Influencing glucocorticoids with AR.
Differentiating treatment induced-neuroendocrine.
Activating AR variants steadily.
Figure: AR signaling axis and mechanisms of AR targeted inhibition.
Here we can see the mechanism of AR signaling and how the prostate cancer is being developed and several AR target inhibitors. The CYP17A1 is the main thing that is causing the conversion of androgen precursors to DHEA and the AD is made from DHEA and this is done by HSD3?1. Testosterone is made from AD with the help of AKR1C3 and ultimately testosterone is converted into DHT by 5?-reductase. When the AR is activated by the DHT a structural modification is seen at the location where the dimerization of AR takes place and after that the translocation of AR occurs towards the nucleus.
And in the nucleus the AR binds with the DNA and then the DNA under goes transcription which results in biologic responses such elevated growth of the prostate, increasing the PSA and the survival rate of the cancer cells.
Anti-androgens are the name given to a diverse group of medicines that counteract the effects of the male sex hormones, testosterone and dihydrotestosterone. The basic principle is some anti-androgens work by lowering the body’s production of androgens while others block androgen receptors, limiting the body’s ability to make use of the androgens produced.
The term ADT is referred to the decrease or inhibition of the gonadal androgen manufacture or signaling. It has been 70 years since this has been a portion of the norm of endeavor for prostate cancer patient. (Huggins and Hodges, 2002). In the early stages medical castration done and after that GnRH agonists were used. Deduction of LH, FSH secretion and testicular testosterone production are the most known disadvantage of such agonists. In addition to that glucocorticoids are used in order to suppress androgen synthesis. Through the invention of AR antagonists which are also known as anti-androgens the activity of androgens can be inhibited. Bicalutamide, flutamide, nilutamide being the first gen antagonists while the enzalutamide is the second gen antagonist. It is seen that Ketoconazole can also block the Cytochrome P450 enzymes by which the testosterone is biosynthesized. Because of being most accurate and powerful blocker of androgen synthesis Abiraterone is being used even though it has been established newly. The synthesis of androgens can be contained in the testes, besides in the cancer cells of prostate gland by Abiraterone. (Pelekanou ; Castanas, 2016)
Among the anti-androgens Enzalutamide belongs to the second generation of drugs and acts of several steps in the AR signaling pathway. Its main action is to inhibit the androgen from attaching to AR and this inhibition in don in competitive manner. The major advantages of Enzalutamide over the 1st gen of anti-androgens are that the translocation of AR can also be blocked by it as well as DNA attachment and co-activator recruitment. The identification of Enzalutamide was made through the quest of finding nonsteroidal anti-androgens that can show activity even when the AR expression amount is very high. (Rodriguez-Vida, Chowdhury, Sternberg, Rudman ; Galazi, 2018)
Confocal microscopy that was done in live LNCaP cells by researchers found that when enzalutamide was used the ratio of nuclear versus cytoplasmic AR was decreased to about fivefold comparing to bicalutamide. They also demonstrated that impairment of nuclear translocation of AR was also done by Enzalutamide. Another study was also done, in this case a VCap cell lines having endogenous AR gene enhancement and CRPC were used. The results were quite good relative to bicalutamide. Apoptosis and growth were found to be subdue by enzalutamide which tells us that enzalutamide was able to show the blocked effect on AR even in CRPC containing situations. (Rodriguez-Vida, Chowdhury, Sternberg, Rudman ; Galazi, 2018)
Figure: Mechanism of action of enzalutamide in the androgen receptor signaling pathway. Obtained from: http://dx.doi.org/10.2147/DDDT.S69433
Here we can see how enzalutamide is giving its anti-androgen effect. Firstly it is competitively inhibiting the testosterone to bind with the AR. The secondly it is inhibiting the nuclear translocation of the AR into the nucleus. Then again lastly enzalutamide is also inhibiting the transcription process of DNA which ultimately leading to the death of the cancer cells.