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Prostate Cancer: The Ion Channels Essay

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Updated: Jul 29th, 2022

Abstract

The present dissertation is about ‘Ion channels in Prostate Cancer’. This topic was selected keeping in view of the incident cases that have become a problematic health issue in Men. The dissertation begins with the epidemiology indicating the rampant characteristics of prostrate cancer with special emphasis on the accumulated data since 25 years and the susceptible ethnic population, debates in mortality rates required diet and genetic factors that control the prostrate cancer. The next aspect is ‘Introduction which gives the basic information on prostrate cancer, important role of prostrate specific antigen and the pathophysiology with reference to androgen dependent and androgen independent nature of prostrate cancer. The dissertation then focuses on types of therapy as it is essential to manage prostrate cancer in view of its complicated nature of invasion and development. As such, various therapies like watchful training, surgery, chemotherapy, hormone therapy, and biological therapy ere highlighted in brief. The next topic is the most central part of the description which is Ion channels.

Here, types of ion channels like potassium channels, voltage gated sodium channels and P2X group of receptors were highlighted. The related key events like the involvement in the membrane potential, cellular proliferation , invasion and metastasis were also detailed in association with he Ion channels. Similarly, the targeting of ion channels for anti-cancer drugs intervention were detailed in brief. The management of prostrate cancer is best possible through a variety of drugs. Hence the next aspect is about the types of drugs their class, mode of action. The final component of the dissertation is summary. This part of description gives the points that were highlighted in the content beginning from the epidemiology of prostrate cancer to its management.

Epidemiology

Prostate cancer is a severe health issue in the recent period. In developed countries like United States, out of 700, 00 incident cancer cases that were recorded annually, 33% constitute prostrate cancer.In other words, approximately 230,000 cases were anticipated of Prostrate Cancer (Gerald, 2006). The highest proportions were reported to be among the US African American and Caucasian men. The detection of prostrate cancer was made feasible through a test to determine prostate-specific antigen (PSA) which gained momentum in 80’s (Gerald, 2006).There were fluctuations between a fall and rise in the detection rate from 1997 to 2000.This also led to controversies on decrease in death rates with the belief that PSA screening raised sharply in contrast to the nature of the disease that gradually stopped (Gerald, 2006)

The debate in the epidemiology of Prostrate Cancer continued to exist in relation to its mortality rates. The detection of cancer development after treatment was faster than before and hence treatment strategies emphasizing on androgen ablation retarded the disease occurrence thereafter enhancing life span (Gerald, 2006)Further, there was unawareness regarding the prevention of the disease as the number of individuals diagnosed with prostrate cancer increased. Epidemiological data revealed basic information with regard to the nutrition and genetic factors, differences in occurrence across various ethnic population and the parameters contributing to the disease with regard to hierarchical clustering (Gronberg, 2003).Therefore, that could be the reason age and race was considered to be significant factors. Genetic component HPC1 gene, tomatoes and their products vitamin D broccoli, selenium have beneficial role to play (Gronberg, 2003).The recent debate in the epidemiological studies is whether or not a patient must undergo a highly sensitive test to detect PSA test following surgery or radio therapy to detect early course of repeated disease occurrence (Gronberg, 2003).

Cancers that occur in men present a serious concern when it comes to the matter of Prostate Cancer that accounts to 10% among the global male cancers(Fitzpatrick, et al., 2009). The burden of this cancer has gradually increased among patient and their relatives due to the complexity involved in the diagnosis and therapy(Fitzpatrick, et al., 2009). This also led to monetary problems for healthcare professionals and policy makers(Fitzpatrick, et al., 2009).Recently, alleviating prostrate cancer risk has drawn attention as per the clinical trial experiments with the type 2 5alpha-reductase (5AR) inhibitor, finasteride(Fitzpatrick, et al., 2009). The increased prevalence, period involved in latency, morbidity and mortality that occur at a significant rate constitute a chosen area for risk minimizing strategies (Fitzpatrick, et al., 2009). The parameters under research for decreasing prostrate cancer are vitamin E and selenium. Selective estrogen receptors and modulators like toremifene (Fitzpatrick, et al., 2009).Similarly, minimizing prostrate cancer by investigating the possible role of Dutasteride is under progress(Fitzpatrick, et al., 2009). Prostate specific antigen (PSA) considered as the main tool to screen men with prostrate cancer has gained significant attention earlier (Payne & Cornford, 2010). Screening although appears expensive could yield precise detection and therapy of prostrate cancer. This is more particularly when prostrate cancers were not identified earlier even with decreased mortality rates (Payne & Cornford, 2010).

PSA serves to evaluate both the localized and metastatic prostrate cancer forms. In Spite of its significance, PSA utility in evaluating castrate-resistant prostate cancer (CRPC) has become a debate with regard to new therapies that have low influence on PSA (Payne & Cornford, 2010). As such, there is need to recognize appropriate biomarker for the detection of prostrate cancer which might ameliorate speed identification, diagnostic perfection, assessing the magnitude of disease progression, therapeutic reliability, especially in latent form of prostrate cancer (Payne & Cornford, 2010).

The pathophysiology of prostate cancer is important to better understand its association with the morbidity and mortality. Prostrate cancer was reported to be androgen dependent disorder (Michael Stanbrough, et al., 2001).Basically, this receptor is a steroid hormone belonging to superfamily of ligand activated transcription factors (Michael Stanbrough, et al., 2001). This receptor was expressed by prostrate cancers for their development. As such, the cancers become androgen dependent and respond well to therapies known as androgen ablation (Michael Stanbrough, et al., 2001). In special circumstances, there would be a recurrence after the therapy when genes specific to AR get amplified and mutations result in the episode of the disease (Michael Stanbrough, et al., 2001). The significance of AR has drawn attention to carry out experiments on animals through androgen administration. AR levels tend to vary with castration. This was revealed when animals were castrated and AR levels decreased and soon increased in epithelial cells on their re-administration (Michael Stanbrough, et al., 2001). This also led to a effect on cell proliferation on the prostrate epithelium. Hence, prostrate cancer becomes AR dependant when androgen-mediated cell proliferation and AR levels are strictly regulated (Michael Stanbrough, et al., 2001). Prostrate cancer also occurs in Androgen independent manner as revealed from autopsy experiments (Rajal, et al., 2006).By employing cDNA expression and tissue microarray analysis novel markers have been identified that include:

  • methylacyl-CoA racemase (AMACR), PIM1, Metastasis associated 1 (MTA1), and enhancer of Zeste homolog 2 (EZH2) (Rajal, et al., 2006). This finding made it clear that heterogeneous phenotypic spectrum of end stage metastatic prostate cancer is androgen independent (Rajal, et al., 2006).

This could be because metastatic cancer was regarded as a plethora of diseases instead of single unit (Rajal, et al., 2006).

Management of Prostate Cancer (types of Therapy)

Prostate Cancer is better managed by various types of therapy. Certain therapies are regarded as standard where as others are under clinical trials.The therapies available on standard basis are as 1. Watchful waiting. This is similar to observing a the circumstances of patient by depriving the treatment unless symptoms manifest. This is common in men of older age especially with other associated medical complications and initial stage disorder.2. Surgery. Generally healthy individuals were preferred surgery as treatment option for prostrate cancer. These are of various types which include Pelvic lymphadenectomy where lymph nodes are taken off in the pelvic region and tissues are examined microscopically for cancer cells. Decision is then taken on the basis of presence or absence of cancer in the lymph nodes to remove prostrate and suggest treatment. Radical prostatectomy: Here, prostrate and its surrounding tissues are surgically eliminated. It may be of Retropubic prostatectomy when prostrate is eliminated by a cut in the abdominal wall region. Perineal prostatectomy, when the prostate is eliminated by a cut done in the perineum. Transurethral resection of the prostate (TURP): Here, tissues are eliminated from the prostate by employing a resectoscope placed in through the urethral region. Men were preferred for this strategy when radial prostatectomy is not possible due to the impact of age and sickness.

Radiation therapy: This is performed by employing x-rays and other types of radiation to destroy cancer cells in order to stop their proliferation. It is of two types. External radiation therapy that utilizes a apparatus out of the body in order to transmit rays toward the cancer cells.‘

In Internal radiation therapy, radioactive substance is used which is present in catheters, needle-like tools etc. These are arranged nearer to tumor cells.

Hormone therapy: This type of therapy eliminates hormonal secretions or inhibits the action to prevent the multiplication of cancer cells. The hormones that are targeted for this purpose are: Luteinizing hormone-Agonists developed for this hormone agonists inhibit the manufacture of testosterone from testicles, for example, leuprolide. Similarly, Antiandrogens inhibit the effect of androgens, for example, flutamide.

Cryosurgery: This type of therapy employs apparatus to enable freezing of cancerous cells and inhibit prostrate cancer.

Chemotherapy: This therapy employs medication or drugs to cease cancer cell proliferation by destroying or blocking the cell division. Chemotherapy when applied orally or administered intravenously drugs reach blood circulation and approach cancer cells overall the body. When given through the spinal column, any organ like abdomen, the drugs reach cancer cells of that region and kill.

Biologic therapy: This involves eliciting or enhancing immunity to combat cancer. Here, the body’s natural defenses are mainly selected for therapy. High-intensity focused ultrasound: Here, ultrasound is used to inhibit cancerous cells and for this purpose an endorectal probe is employed especially to produce sound waves of high energy. Proton beam radiation therapy: This therapy employs radiation with increased energy that kills tumors with proton beam. This therapy is extensively used in treating prostate cancer. In some cases, clinical trials offer a good treatment strategy. As one of the options of cancer research, this option is performed to determine whether the novel cancer therapies are safer and reliable when compared to the well accepted conventional treatment options. However, with the emerging trends in the treatment option a follow up study is always essential to better rule out the efficacy.

Recent advancements in research has led to the development of devising therapies keeping in view of ion channels. These components of signal transduction pathways play important role as valuable conductance tools for cancer cells, hematopoietic stem cells and other proliferating cells (Conti, 2007).Their help in the prognosis and categorization of cancerous cells has achieved good progress(Conti, 2007). The ion channels have a property of correcting the defects in cancer cell proliferation. This function is especially taken up by inhibitors and modulators specific of ion channels (Conti, 2007). Ion channels could be manipulated for better conductances of cellular ions with electromagnetic properties. (Conti, 2007).There are still concerns whether ion channels have significance in the field of clinical oncology (Conti, 2007).

Arcangeli, et al., (2009) recently described that targeted therapy is gaining momentum with regard to the prognosis of cancer. The machinery that controls the setup and development of various tumors has become particular and drawn the attention of pharmacological interventions (Arcangeli, et al., 2009).

The progression in cancer is best understood from the expression patterns and function of various ion channels. Ion channels play a central role in regulating proliferation of cells and programmed cell death, cellular invasion and metastasis. Potassium channels were considered to posses’ good scientific evidence (Arcangeli, et al., 2009).This could be because their expression pattern in the beginning stage of human cancers is subjected to deviate and they tend to show an effect of pleiotropism on the cell physiology (Arcangeli, et al., 2009). This was evident from their function of membrane potential on calcium fluxes of the cellular machinery (Arcangeli, et al., 2009). They also exert their function on mitotic cell division which in turn relies on cell volume regulation in association with chloride channels (Arcangeli, et al., 2009).

On the whole, ion channels are best characterized in their roles in controlling cell motility, facilitating cellular matrix cooperation and by enhancing angiogenesis (Arcangeli, et al., 2009). The flow of signaling information in cells gets stimulated when ion channels make protein network with membrane bound proteins like growth factor receptors or integrins.The deviation in the expression of channels was better made use in the diagnostic field in order to target compounds to a particular cancerous tissue.In addition, the channel activity when gets inhibited would alter the development of certain tumors (Arcangeli, et al., 2009).

This strategy led to a novel application in Biomedical science which in turn placed emphasis on the utility of peptide toxins, small interfering RNAs, antisense oligonucleotides, blocking antibodies, and various other small organic compounds(Arcangeli, et al., 2009).However, there are certain concerns in utilizing ion channels.This due to the fears of side effects like cardiac arrhythmias certain ion channel blockers bring about(Arcangeli, et al., 2009).As such, therapeutic interventions were focused at generating harmless compounds by unwinding ion channels from the network of multiprotein signaling membranes (Arcangeli, et al., 2009).

There are various channels that affect the development of prostate cancer. These include Potassium channel, sodium channel and P2X receptors. There is need to know about these channels in detail. Potassium channels with TREK-1 two-pore domain (K(2P)) posses electricity which is independent of voltage and time (Voloshyna, et al., 2008). These channels have been associated with proliferation of cells and certain channels are even show hi9gh expression in certain neoplasms Voloshyna, et al., (2008). The expression of TREK1 was tightly associated with the magnitude of disease progression (Voloshyna, et al., 2008).

This was revealed when cell lines specific to prostrate cancer have expressed TREK1 whereas there was no expression in normal or benign hyperplasia (Voloshyna, et al., 2008). Therefore potassium channels of TREK1 would be considered as new markers and targets in protract cancer. In another report, it was described that two-pore-domain background potassium (K(2P)) channels play important role in the function of membrane potential and cell excitability. Studies in mouse models have furnished insights on the ability of potassium channels in the physiology (Bayliss & Barrett 2008). This was revealed when mice were deleted of K(2P)-channel subunits especially of TASK and TREK subgroup. The stimulation of K(2P) channels by anesthetics drugs TASK-1, TASK-3 would lead to immobilization and hypnosis (Bayliss & Barrett 2008). The TASK channels were important for the maintenance of homeostasis with regard to the control of adrenal aldosterone secretion (Bayliss & Barrett 2008). Further TREK-1 channels exert their their effect on temperature and pain sensation, mood control, neuroprotection by fatty acids(Bayliss & Barrett 2008). These are specific to lipid activated TREK- 1 channel function. On the other hand, TASK -2 channels of alkaline origin are important for bicarbonate reabsorbtion and osmoregulation in the proximal tubule of kidneys (Bayliss & Barrett 2008).

The other channels to be reported are sodium channels. These are exploited for their valuable potential in studying the metastasis of invasive origin like the androgen-dependent LNCaP (Bennett, Smith, & Harper, 2004). The related cell lines C4 and C4 -2 were developed and reported to be tumorogenic, and androgen-independent

(Bennett, Smith, & Harper, 2004). It was revelaed that C4 and C4-2 cells are have more invasive function than LC (Bennett, Smith, & Harper, 2004). These sodium channels enhance the cell line with increase invasive potential which could be further inhibhited by therapy with tetrodotoxin (TTX) which is considered as voltage-gated sodium channel inhibitor (Bennett, Smith, & Harper, 2004).

.Therefore, voltage-gated sodium channel expression plays important role in the enhanced invasive potential of human prostate cancer cells(Bennett, Smith, & Harper, 2004). Similarly, cell lines expressing human adult skeletal muscle sodium channel Na(v1.4) have exhibited the numbers of LC, C4, and C4-2 cells that have invading potential (Bennett, Smith, & Harper, 2004). This strategy was found decreased by therapy with TTX (Bennett, Smith, & Harper, 2004). Hence, voltage gated sodium channels play role in improving the invasive potential of non-metastatic (LC cells) and also aggressive cells like C4 and C4-2 cells (Bennett, Smith, & Harper, 2004).

Thus, enhanced voltage-gated sodium channel when expressed independently is essential to improve invasiveness of prostrate cancer cell lines which are other wise considered as tools for studying metastasis (Bennett, Smith, & Harper, 2004).The next significant ion channels implicated in the pathophysiology of Prostrate cancer are P2X(7) receptors (Slater, et al., 2004). These are important as their presence in the normal prostrate cancerous tissue enables the direct tumor biopsy with decreased complexity for studying diagnosis and progression of cancer enables cancer(Slater, et al., 2004). This was revealed when P2X(7) receptors were found missing in the epithelial region of prostrate tissues of post mortem bodies and tissue of transurethral resection obtained from young individuals(Slater, et al., 2004). P2X(7) receptor was found in normal epithelial cells of acini but also found in detectable manner in the nucleus, proceeding towards cytoplasm and getting accumulated over the apical membrane of cancerous epithelial cells(Slater, et al., 2004).In another study, it was reported that the apoptotic calcium channel receptor P2X(7) are associated with prostate-specific antigen (PSA) levels(Slater, et al., 2004).

Earlier, in prostrate cancerous cells P2X1 and 2 receptors were although reported to be absent in normal prostrate epithelium which would not proceed towards prostrate cancer. In contrast, progressing prostrate cancer cells, P2X (1 )and P2X(2) receptors were found in slow manner beginning with the nucleus, cytoplasm and proceeding towards apical epithelium, as prostate cancer progressed(Slater, et al., 2004).

This was observed even before the detection of cancer by Gleason grading confirmed by H and E staining(Slater, et al., 2004).. Similarly, P2X7 receptors yielded confounding results and agreed with P2X(1) and P2X(2) expression patterns(Slater, et al., 2004).. The employment of tool like radical prostatectomy and biopsies, enabled to study the variations in calcium channel metabolism (Slater, et al., 2004).. Hence, the prostrate tumor may be identified without the requirement of need for direct tumor samples, which might unnecessarily contribute to the identification of leading to false negative cases not detected by H or E stain (Slater, et al., 2004). PSA levels were reported to be associated with P2X (7) labeling. As such, all patients found with P2X(7) expression, also shown positive H and E stain, with PSA levels > 2(Slater, et al., 2004).. Hence, high PSA levels were reported to be perfect biomarkers of may be an accurate cancer progression(Slater, et al., 2004). This has strengthened the role of P2X group of receptors in prostrate cancer. Next, there is also a further need to know about the precise behavior of ion channels. Basically, the ion channel of plasma membrane offer a variety of basic cellular processes, like maintenance of homeostasis in terms of cellular proliferation, differentiation, and apoptosis(Prevarskaya, et al.,2007).

An increase in these functional roles of proliferation or an aberrant differentiation, altered function to meet the death could be considered as the main reasons for aberrant tissue growth, that could gradually turn into uncontrolled proliferation, invasiveness , and cancer (Prevarskaya, et al.,2007).As mentioned previously, Prostate cancer cells show various ion channels on their plasma membrane. An efflux of ionic changes, intracellular ionic concentrations that get altered cell volume control, are all essential features of ion Channels (Prevarskaya, et al.,2007). High cancerous nature and invasive potential of androgen-independent prostrate cancer cells is

related to a ‘more excitable’ phenotype of their plasma membrane(Prevarskaya, et al.,2007). This is accomplished by the presence of of voltage-gated Na(+) and Ca(2+) channels that control Ca(2+) influx, abnormal expression patterns of different K(+) channels and members of the Transient Receptor Potential (TRP) channel family, and high potential for the establishment of constant volume (Prevarskaya, et al.,2007).

Treatment

Ion channels lay important role as their molecular targets for anticancer drug development. Due to he complicated signaling pathways involved in the cancer metastasis the ion channels that were described have long been investigated in various clinical trials potential therapeutic targets (Le Guennec, et al., 2007). Since transmembrane proteins, along with ion channels, have role in the disease progression, proliferation, migration and invasion have become the thirst areas of research. (Le Guennec, et al., 2007).The protein’s role in non cancerous cells and in excitable cells has been under investigation (Le Guennec, et al., 2007). Thus ion channels have been emphasized in research with regard to proliferation, migration and invasion that play central role in the tumor progression (Le Guennec, et al., 2007).

There ae a variety of anticancer drugs. These are Avodart Oral. This drug belongs to class of 5 alpha reductase inhibitors(www.medicalnewstoday.com). This medication is used to shrink an enlarged prostate in men with a condition called benign prostatic hyperplasia (www.healthcentral.com). It functions by reducing the hormone levels crucial for the development of prostate (dihydrotestosterone). Dutasteride reduces urinary blockage and improves urine flow (www.healthcentral.com. ) Bactrim Oral. This drug belongs to class of Folic Acid Antagonist (www.drugs.com/cons/bactrim.html).This medication is a combination of two antibiotics used to treat a wide variety of bacterial infections (e.g., middle ear, urine, respiratory and intestinal infections) (www.healthcentral.com). It is also used to prevent and treat a certain type of pneumonia (pneumocystis-type). (www.healthcentral.com) Cardura XL Oral. This drug belongs to class of Alpha-1 Adrenergic Blocker. This medication is used to treat the symptoms of a condition of the prostate gland called BPH (benign prostatic hyperplasia, also known as enlarged prostate) (www.healthcentral.com). It is an alpha blocker that works by relaxing the muscles in the bladder neck and prostate (www.healthcentral.com) Relaxing these muscles leads to relief of symptoms of BPH such as the feeling of needing to urinate frequently or urgently, weak stream, difficulty in beginning the flow of urine, and the need to urinate during the middle of the night. (www.healthcentral.com).

Summary: Prostrate cancer plays important role among the heath issues that concern the modern world today. It has emerged as the severe cancer in developed countries like United States where it is most prevalent with a proportion of 33%. Ethnicity has a part in the occurrence as the disease may be more common in African Nationals of Unite States and Caucasian men. The research on prostrate cancer has been in progress since 25 years where emphasis was first given to the detection of prostate-specific antigen (PSA). Controversies have also emerged due to inconsistent data on mortality rates.

However, intervention programs have shed light on the need of investigations on nutrition with reference to tomatoes, vitamins D and E, broccoli, selenium and HPC1 gene. Understanding the pathophysiology of prostrate cancer is complex due to the molecular machinery involved in the cellular events. This disorder is associated with the hormone receptors specific to steroid androgen. The expression of Androgen receptor was considered important as it contributes to proliferation of cells on the prostrate epithelium. This disorder is also androgen independent due to the involvement of various genetic factors as revealed by cDNA expression and tissue microarray analysis. This led to heterogeneity in its pathogenesis. Hence, prostrate cancer is androgen dependent and independent. There are various types of therapies available for the management of Prostrate cancer. These are watchful waiting, surgery, radiation therapy, chemotherapy, Biological therapy, and hormonal therapy. The area of prostrate cancer that was much investigation is Ion Channels. There are of potassium channels, voltage gated sodium channels and P2X receptors. Potassium channels with TREK-1 two-pore domain (K(2P)) were reported to play role in proliferation of cells. They have implication as novel markers in protract cancer. Their contribution to the function of membrane potential, maintenance of homeostasis, cell excitability, bicarbonate flow and osmotic balance in kidneys is also interesting. Similarly, voltage gated sodium channels have important role in prostrate cancer as revealed from experiments on cell lines. As these channels improve the invasiveness, they were targeted with drugs like tetrodotoxin (TTX) which is a voltage-gated sodium channel inhibitor.

The next important are P2X(7) receptors found in the epithelial region of prostrate tissues of acini and in nucleus, tissues progressing towards cytoplasm. This channel is connected to prostate-specific antigen (PSA) levels.

In view of the above molecular machinery, therapeutic interventions have started with emphasis on ion channels and signaling pathways involved in the cancer metastasis. Ion channels in association with transmembrane proteins, have exclusively rargeted due to their involvement in cell proliferation, migration and invasion. Further, from the above description, it can also be inferred that the spread of cancer to a distant site could be better alleviated by the study of signaling pathways. Since a variety of factors may be involved that contribute to the localization and metastasis of caner , there is need to dissect the relationship between the key molecular events and the outcome. This can be better characterized by novel markers that furniosh insights on the gene expression when down or upregulated. Therefore, the risk of prostrate cancer can be better minimized in the society if intervention programs are implemented in an evience based practice approach.

References

Arcangeli, A.,, Crociani, O., Lastraioli, E., Masi, A., Pillozzi, S., Becchetti, A. 2009, 16(1),pp.66-93.

Bayliss, D,A., Barrett, P,Q.2008. Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact. Trends Pharmacol Sci,29(11),pp.566-75

Bennett, E,S., Smith, B,A., Harper, J,M. 2004. Voltage-gated Na+ channels confer invasive properties on human prostate cancer cells. Pflugers Arch, 447(6),pp.908-14.

Conti, M. 2002.Targeting ion channels for new strategies in cancer diagnosis and therapy. Curr Clin Pharmacol, 2(2), pp.135-44.

Fitzpatrick, J.M., Schulman, C., Zlotta, A.R., Schröder, F.H.2009. Prostate cancer: a serious disease suitable for prevention. BJU Int, 103(7), pp.864-70.

Gerald Chodak. 2006. Prostate Cancer: Epidemiology, Screening, and Biomarkers. Rev Urol, 8(suppl 2):ppS3-S8.

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Le Guennec, J,Y., Ouadid-Ahidouch, H., Soriani, O., Besson, P., Ahidouch, A., Vandier, C.2007. Voltage-gated ion channels, new targets in anti-cancer research. Recent Pat Anticancer Drug Discov,2(3),pp.189-202.

Michael Stanbrough, Irwin Leav, Paul W. L. Kwan, Glenn J. Bubley, and Steven P. Balk.2001.Prostatic intraepithelial neoplasia in mice expressingan androgen receptor transgene in prostate epithelium. PNAS, 98 (19).pp. 10823–10828.

Payne, H. & Cornford, P. Prostate-specific antigen: An evolving role in diagnosis, monitoring, and treatment evaluation in prostate cancer.2010. Urol Oncol. Jan 6. [Epub ahead of print].

Prevarskaya, N., Skryma, R., Bidaux, G., Flourakis, M., Shuba, Y. 2007.Ion channels in death and differentiation of prostate cancer cells. Cell Death Differ,14(7),pp.1295-304.

Prostate cancer: a serious disease suitable for prevention.Fitzpatrick, J.M., Schulman, C., Zlotta, A.R., Schröder, F.H.2009. Prostate cancer: a serious disease suitable for prevention. BJU Int, 103(7), pp.864-70.

Rajal, B. Shah, Rohit Mehra, Arul, M. Chinnaiyan, Ronglai Shen, Debashis Ghosh, Ming Zhou, Gary R. MacVicar, Soorynarayana Varambally, Jason Harwood, Tarek ,A. Bismar, Robert Kim, Mark, A.Rubin & Kenneth, J. Pienta. Androgen-Independent Prostate Cancer Is a Heterogeneous Group of Diseases Lessons from a Rapid Autopsy Program. Cancer Res, 64(24), 9209-16.1.

Slater, M., Danieletto, S., Gidley-Baird, A., The, L.C., Barden, J.A.2004. Early prostate cancer detected using expression of non-functional cytolytic P2X7 receptors. Histopathology,44(3),pp.206-15.

Voloshyna, I., Besana, A., Castillo, M., Matos, T., Weinstein, I.B., Mansukhani, M., Robinson, R.B., Cordon-Cardo, C., Feinmark, S.J. 2008. TREK-1 is a novel molecular target in prostate cancer. Cancer Res,68(4):1197-203.

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