One of the subjects I investigated during the past weeks is the role of androgen in cancer. Androgen receptors (AR) blockage is a treatment strategy used in e.g. prostate cancer, in order to stop or reduce cancer progression. However, as you will see from the papers cited below, and these are just a few out of a large number of publications on this subject, the androgen receptor has a very important role in tumor progression and its blocking alone may lead to cancer cell death in many tumor types.
I actually believe that just like for every problem there are multiple ways to solve it, hormones is one of the angles that is relevant for all cancers capturing a solution to every type of cancer. The difficulty is that there are so many hormones in the human body, interconnected like a spider web. However, beyond this complexity, it has been shown that e.g. thyroid hormones, and more specifically T4 (inhibition) may hold the answer to many types of cancers. (Ref.).
The high relevance of hormones for the human body is undebatable since hormones may even define who we are, how we think and how we look. At cellular level, hormones have impact on mayble all intracellular mechanisms, controlling even the membrane proton pumps such as Na/H exchange (Ref.), pumps that are highly relevant in cancers (Ref.).
Back to androgen receptors, I like the idea of focusing on AR blockage because that can be done relatively easy with various FDA approved drugs that have a well known safety profile. Wouldn’t be great if with one single and safe pill taken every day we could eliminate cancer? As you will see in the references below, that actually happened in patients with e.g. adrenal tumor and breast tumor. I am sure that if I search I will find many more case reports but the references below are enough to demonstrate the concept.
Relevant References and Case Reports in Humans:
Androgen Receptor as a Driver of Therapeutic Resistance in Advanced Prostate Cancer http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062951/
Androgen receptor-blocking agents: potential role in pancreatic cancer. http://www.ncbi.nlm.nih.gov/pubmed/11043816/ Confirmatory evidence has now come from a double-blind, placebo-controlled trial in patients with pancreatic cancer in which flutamide, the pure androgen receptor blocker, doubled survival duration over control patients.
Androgens Up-regulate the Insulin-like Growth Factor-I Receptor in Prostate Cancer Cells http://www.ncbi.nlm.nih.gov/pubmed/15753383 Agents targeting these signaling pathways (ERK ) or the IGF-IR itself should therefore be considered as a complement of standard anti-androgen therapy to induce tumor regression and possibly reduce the chance or delay the time of tumor progression to androgen independence.
The androgen receptor as an emerging target in hepatocellular carcinoma http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918288/
Androgen receptor signaling regulates growth of glioblastoma multiforme in men. http://www.ncbi.nlm.nih.gov/pubmed/25315188
Complete Response of Metastatic Androgen Receptor–Positive Breast Cancer to Bicalutamide: Case Report and Review of the Literature http://jco.ascopubs.org/content/34/4/e21.full Approximately 10% to 32% of TNBC have androgen receptor (AR) expression.
Multiple Molecular Subtypes of Triple-Negative Breast Cancer Critically Rely on Androgen Receptor and Respond to Enzalutamide In Vivo http://mct.aacrjournals.org/content/14/3/769 Our study indicates that multiple subtypes of AR+ TNBC depend on AR for proliferation, migration, and invasion, and tumor growth in vivo and provides promising preclinical data on the efficacy of enzalutamide in TNBC with low AR expression.
Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer. http://www.ncbi.nlm.nih.gov/pubmed/27120467 Surprisingly, we found that AR antagonists inhibited proliferation of most BC cell lines in an AR-independent manner, raising questions regarding their mechanism of action. As VDR agonist they used Calcitriol.
Disappearance of a virilizing adrenal tumor following therapy with cyproterone acetate. http://www.ncbi.nlm.nih.gov/pubmed/16322333 As the patient refused surgery, virilization was treated with the antiandrogen cyproterone acetate (CPA), but for only 4 months because clinical and hormone abnormalities reversed and the tumor was no longer visible. The patient remains symptom-free. This first report of a curative effect of CPA on a purely virilizing adrenal tumor opens new avenues in the management of such tumors.
Androgen receptor inducing bladder cancer progression by promoting an epithelial-mesenchymal transition. http://www.ncbi.nlm.nih.gov/pubmed/24329492 It is concluded that suppression of AR expression decreased the production of TGF-β, inhibiting EMT and bladder cancer cell growth in vitro and in vivo, implying that its use might be a potential therapeutic target for the treatment of bladder cancer.
Source and Dose:
One example of AR blocker is Cyproterone Acetate, a substance that is also used in contraceptive pills. Cyproterone Acetate is cheap and available in most countries via local or online pharmacies. Some online pharmacies are selling it even without prescription. The dose that is typically used for contraceptive pills is in the range of a few mg/day while that used to block androgen receptors is in the range of 10 to 200mg/day. Because Cyproterone Acetate can also lead to some toxicity on the liver, I would prefer to stay in the 50mg/day dose range but you would need to check with your doctor.
Note that besides, Cyproterone Acetate there are many other androgen receptor blocking drugs commercially available. (Ref.) Even Cimetidine (an anti histamine safe drug that is a must in my view for every cancer patient to reduce chance for metastasis) seems to have anti androgen activity (Ref.).
However, in some cases, androgen receptor blockers may not be enough (Ref.). In that case, to have an effective treatment strategy, we may need to also reduce androgen production. This is typically done with drugs such as Ketokonazole, Abiraterone Acetate, etc. that reduce hormone production by inhibiting relevant enzymes at cellular level but also with GnRH modulators (discussed in an earlier post on this website) that lead to inhibition of the circulating hormones (released from the brain) and that in turn trigger the androgen production in adrenals and reproductive glands. Indeed, GnRH modulators alone are used by some clinics to treat various tumor types (Ref.).
Androgens such as testosterone are synthesized primarily by the Leydig cells in the testes, under the regulation of luteinizing hormone (LH) produced by the anterior pituitary gland. LH secretion is in turn regulated by gonadotropin-releasing hormone (GnRH). Once produced, testosterone mostly circulates in the blood bound to serum sex hormone-binding globulin (SHBG) and albumin (Ref.)
Androgen Receptor blockers are also used in the treatment of hirsutism and other androgen-dependent conditions and as a component of hormone replacement therapy for transgender women. The drugs act as selective antagonists of the androgen receptor (AR), preventing androgens like testosterone and dihydrotestosterone (DHT) from binding to and activating the AR and exerting their biological effects in the body.
However, besides testosterone and dihydrotestosterone pathways, androgen receptors are facilitating many other cellular processes in the human body, of which some are very relevant to cancer development:
Transcription_Androgen Receptor nuclear signaling:
Source for the above figure: http://lsresearch.thomsonreuters.com/maps/2202/
Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer. http://www.ncbi.nlm.nih.gov/pubmed/27557496
Androgen receptor (AR) and PI3K/AKT/mTORC1 are major survival signals that drive prostate cancer to a lethal disease. Reciprocal activation of these oncogenic pathways from negative cross talks contributes to low/limited success of pathway-selective inhibitors in curbing prostate cancer progression. We report that the antibiotic salinomycin, a cancer stem cell blocker, is a dual-acting AR and mTORC1 inhibitor, inhibiting PTEN-deficient castration-sensitive and castration-resistant prostate cancer in culture and xenograft tumors. AR expression, its transcriptional activity, and androgen biosynthesis regulating enzymes CYP17A1, HSD3β1 were reduced by sub-micro molar salinomycin. Estrogen receptor-α expression was unchanged. Loss of phosphorylated AR at serine-81, which is an index for nuclear AR activity, preceded total AR reduction. Rapamycin enhanced the AR protein level without altering phosphoAR-Ser81 and CYP17A1. Inactivation of mTORC1, evident from reduced phosphorylation of mTOR and downstream effectors, as well as AMPK activation led to robust autophagy induction. Apoptosis increased modestly, albeit significantly, by sub-micro molar salinomycin. Enhanced stimulatory TSC2 phosphorylation at Ser-1387 by AMPK, and reduced inhibitory TSC2 phosphorylation at Ser-939/Thr-1462 catalyzed by AKT augmented TSC2/TSC1 activity, which led to mTORC1 inhibition. AMPK-mediated raptor phosphorylation further reduced mTOR’s kinase function and mTORC1 activity. Our novel finding on dual inhibition of AR and mTORC1 suggests that salinomycin is potentially active as monotherapy against advanced prostate cancer.
Androgen receptor: structure, role in prostate cancer and drug discovery http://www.nature.com/aps/journal/v36/n1/full/aps201418a.html
Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.
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