Role Of Nitric Oxide Synthase In Cancer Biology
The roles of NOS and NO on DNA damage, apoptosis, cell cycle, enhancement of cell proliferation, angiogenesis and metastasis are currently viewed, and NO was found to be associated with tumor environment, for example, the vasculature cells and other stromal cells . Research also indicated that NOS2 expression was correlated with tumor vascularization, accumulations of p53 mutations and activation of epidermal growth factor receptor, even could be treated as an independent predictor of poor survival in women with estrogen receptor -negative breast tumors . Low concentrations of NO acted as a promotional role in angiogenesis which stimulates tumor progression by providing blood flow access to the tumor and subsequently resulting in cell proliferation. On the contrary, high levels of NO tend to be cytotoxic to cancer cells . While in animal models, iNOS overexpression produced either pro-tumor or anti-tumor effect on tumor growth, these alterable effects seem to be dependent on the tumor microenvironment and the tumor type itself . The effects of NO possibly differ in expression level of iNOS, duration and timing of NO delivery, the microenvironment, the genetic background and the cell type .
Figure 3.
Nos And Prostate Carcinoma
Prostate carcinoma is one of the most common cancers among men and second in cancer-related deaths in the United States. An estimated study predicted that there will be 180, 890 new prostate carcinoma cases and 26, 120 deaths due to the disease in the country in 2016 . Etiological studies implicated that multiple reasons involved in prostate carcinoma susceptibility, such as dietary, environment, hormone status and genetic factors . Growing studies indicated that NOS and NO system play crucial roles in progression of human prostate carcinoma .
The physiological functions of NO are dependent primarily on concentrations. Low concentration of NO acted as a signal transducer and affects many physiological processes including blood flow regulation, platelet activity, iron homeostasis, cell proliferation and neurotransmission, whereas, in high concentrations, it exerted a cytotoxic protective effect, for example, to against pathogens and perhaps tumors .
Nonsurgical Treatment For Enlarged Prostate On The Horizon
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- Parsemus Foundation
- Summary:
Enlarged prostate is a common problem in older males . Parsemus Foundation sponsored a study by Dr. Raffaella Leoci to investigate a potential new non-invasive treatment in dogs with benign prostatic hyperplasia. The method was very effective at reducing the size of the prostate gland and we expect that it is relevant for human use too.
The study was just published in the journal The Prostate.
What is benign prostatic hyperplasia?
BPH results from urogenital aging. Recent studies suggest that an age-related impairment of the blood supply to the lower urinary tract plays a role in the development of BPH and thus may be a contributing factor in the pathogenesis of BPH.
Simple and effective treatment for canine prostate disease could also help humans
The new method used in the study to treat dogs with BPH was pulsed electromagnetic field therapy . PEMF is a noninvasive method that generates both an electrical and magnetic field and is used in orthopedics, neurology, and urology. It has been reported to have an anti-inflammatory effect and increases healing and blood circulation. The idea of using this method for BPH is to improve prostate blood flow and reduce the size of the prostate gland.
How does pulsed electromagnetic field therapy work?
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Nitric Oxide What Is It Exactly
Nitric Oxide is a signaling molecule that takes part in virtually every organ and cellular function in the body.
For example, in the cardiovascular system, it controls vascular tone, , relaxes the vascular smooth muscle, and ensures greater blood flow.
For the immune system, it can modulate T cell-mediated immune response and keep the body in excellent shape. Because of its vasodilatory effect, nitric oxide provides a healthy blood flow to the kidneys.
The body creates nitric oxide by itself with the help of different mechanisms, a study shows. From L-arginine, an amino acid that aids with enzyme nitric oxide synthase. And from inorganic nitrates, commonly found in certain foods.
As you can see, this small gaseous molecule has multiple uses. But, there is more to its blood flow-boosting properties. Nitric oxide can come in handy for prostate health as well.
The Role Of No In Inflammation
Inflammation is well known to be a precursor to carcinogenesis in many organs, including the prostate, and NO plays a central role in this. In experimental studies, iNOS has been increased in a number of inflammatory-related cancers, including Barretts esophagus and esophageal carcinoma. The study of NO in inflammatory-promoted carcinogenesis has given further insight into the role of NO in cancer and how therapies may incorporate this molecule, and its downstream effects, in the future . By using NO as an inflammatory mediator, the role that inflammation plays in cancer can be mediated by NO-based therapies.
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Nitric Oxide Donors For Prostate And Bladder Cancers: Current State And Challenges
Nitric oxide is an endogenous molecule that plays pivotal physiological and pathophysiological roles, particularly in cancer biology. Generally, low concentrations of NO lead to tumor promotion. In contrast, high NO concentrations have pro-apoptotic functions, leading to tumor suppression, and in this case, NO is involved in immune surveillance. Under oxidative stress, inducible NO synthase produces high NO concentrations for antineoplastic activities. Prostate and bladder cancers are the most commonly detected cancers in men, and are related to cancer death in males. This review summarizes the state of the art of NO/NO donors in combating prostate and bladder cancers, highlighting the importance of NO donors in cancer treatment, and the limitations and challenges to be overcome. In addition, the combination of NO donors with classical therapies in the treatment of prostate and bladder cancers is also presented and discussed. The combination of NO donors with conventional anticancer drugs is reported to inhibit tumor growth, since NO is able to sensitize tumor cells, enhancing the efficacy of the traditional drugs. Although important progress has been made, more studies are still necessary to definitely translate the administration of NO donors to clinical sets. The purpose of this review is to inspire new avenues in this topic.
European journal of pharmacology. 2018 Mar 01
Amedea B Seabra, Nelson Durán
The Role Of No In Inflammatory Processes In Prostate Cancer
Prostate cancer is promoted by inflammation, of which iNOS is an important player . ROS damage and downregulated antioxidants are risk factors for PIN and prostate cancer, and oxidative damage is found in greater quantities in cancerous versus normal prostatic epithelium. Antioxidants such as copper-zinc oxide dismutase and manganese superoxide dismutase are reported to have lower expressions in the epithelium of PIN and prostate cancer . NO is shown to inhibit AR activity in a dose-dependent manner. This is mediated through nitrosative stress, likely the S-nitrosylation of the zinc fingers, preventing AR from binding to DNA . Some argue that this action may only inhibit the proliferation of AR-dependent cancers and create a selection pressure promoting the growth of AR-independent cancers . This line of reasoning could provide mechanistic support for previous assertions linking increasing iNOS expression with inferior survival in prostate cancer . At the same time, however, the knowledge that NO can prevent the intracellular DNA binding of the AR may have implications not just for androgen-sensitive tumors but also for CRPC.
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Nos And Sperm Function
Approximately 15% of couples suffer from infertility while male cause contributed to nearly 50% in these infertile couples . Male reproduction is known to involve complicated aspects, such as spermatogenesis, sperm dynamics, sperm morphology and acrosome reaction. Increasing evidences have been indicating that NOS and NO are associated with male infertility .
3.2.1. Sperm motility, morphology and viability
3.2.2. Capacitation, hyperactivation and acrosome reaction
Capacitation is a process in which spermatozoa acquire the ability to bind to the eggs zone pellucida and fertilize an oocyte during their transit in the female genital tract . Capacitation involves in some molecular events, and it was clear that low level of NO from NO-releasing agents induces human sperm capacitation . Indeed, it has been reported that NO-releasing compounds significantly benefit the capacitation, whereas NO inhibitors decrease this process . In fact, NO produced by spermatozoa involves in a cascade of molecular events of capacitation, which is needed over the course of this process .
3.2.3. Sperm mitochondria
Prostate Cancer And No Therapeutics
The theoretical underpinning of NO therapies is progressing well, as the in vivo and in vitro studies mentioned previously have shown positive effects of NO therapy on cancer. The practical development of NO-releasing drugs is the obvious but challenging next step. There are several different methods of using NO as a drug, but the method of delivery must be tailored so that the proper concentration is delivered for the correct duration to create the desired effect . Methods are also available to limit the amount of NO available to cells. These methods include viral transfection of genes, cell-based methods, NO prodrugs, free radical scavengers, and pharmacologic inhibition of NOS and/or NO itself. The NO dose necessary for cytotoxicity is generally 10100 times greater than the dose for tumor promotion . While the first challenge of NO-based therapy is dose modulation, the other major challenge is how to direct the NO to the tumor cells and avoid systemic toxicity .
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Possible Therapy Strategies Of Nos On Male Infertility
Increasing evidences has been showing that inappropriate concentration level of NO may contribute to male infertility in some extend by means of decreasing sperm motility and normal sperm morphology, reducing efficiency of capacitation and acrosome action. It is reasonable to consider possible therapy strategies to the utilization of NOS donors or inhibitors so that to adjust the concentration of NO to the right level. In fact, significantly higher fertile rate was observed in animal experiment in vitro, and further researches would be needed to warrant the potential benefits for human beings.
Isolated Pcscs Display Enhanced Enos
Fig. 3
We next sought to determine the expression profile of eNOS in PCSCs-enriched 3D-cultured spheroids. Expression analysis showed that the 3D-cultured spheroids derived from different prostate cancer cell lines expressed significant higher eNOS expression in both mRNA and protein levels, of which levels returned to low levels after re-adherent differentiation culture . Microscopic detection of intracellular NO by DAF-DM confirmed that the PCSCs-enriched 3D-cultured spheroids displayed higher intracellular NO level than their corresponding counterparts under adherent 2D culture . Moreover, PCSCs isolated by SORE6-GFP reporter-based FACS sorting of different prostate cancer cell lines showed that SORE6+ cells expressed significant higher level of eNOS than SORE6 cells . Similarly, PCSCs isolated by anti-CD133-based FACS sorting further confirmed that PCSCs derived from primary prostate cancer cultures expressed higher level of eNOS . Together, these results indicate that PCSCs isolated from either prostate cancer cell lines or primary prostate tumor cultures exhibited enhanced eNOS-NO signaling or activity.
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In Vitro Growth Analyses
Cell viability assay. Single-cell suspensions were prepared from monolayer cell cultures and seeded on 96-well plates at a density of 1×104 cells/well. After 24 h, cultured cells were treated with different drugs or control vehicle for 4872 h. The viable cells were determined by a colorimetric cell viability assay as described previously . Wound healing assay. Cell migration capacity of PC-3 M-eNOS/PC-3 M-sh-eNOS/PC-3 M-vector-transduced cells were evaluated by wound healing assay followed procedure as described previously . Briefly, cells were seeded onto poly-L-lysine-coated 6-well plates to grow to confluent monolayers for 24 h. Monolayers were starved in serum-free medium for 24 h before making straight scratches using 200-l pipette tips. After washing with medium to remove cell debris, wounded monolayers were incubated in medium with 1% FBS to minimize cell proliferation. The wound gaps were photographed using a phrase-contrast microscope at regular intervals between 0 and 41 h, and the area of scratches was measured using ImageJ software . Assays were repeated at least in three independent triplicates.
Abstract: Nitric Oxide Is A Ubiquitous Water Soluble Free Radical Gas Which Plays Key Role In Various Physiological As Well As Pathological Processes Over Past Decades No Has Emerged As A Molecule Of Interest In Carcinogenesis And Tumor Growth Progression However There Is Considerable Controversy And Confusion In Understanding Its Role In Cancer Biology It Is Said To Have Both Tumoricidal As Well As Tumor Promoting Effects Which Depend On Its Timing Location And Concentration No Has Been Suggested To Moshow More
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Neutrophils are myeloid cells that constitute 50-70 % of all white blood cells in the human circulation. Traditionally, neutrophils are viewed as the first line of defense against infections and as a major component of the inflammatory process. In addition, accumulating evidence suggest that neutrophils may also play a key role in multiple aspects of cancer biology. The possible involvement of neutrophils in cancer prevention and promotion was already suggested more than half a century ago, however, despite being the major component of the immune system, their contribution has often been overshadowed by other immune components such as lymphocytes and macrophages. Neutrophils seem to have conflicting functions in cancer and can be classified into anti-tumor and pro-tumor sub-populations. The aim of this review is to discuss the varying nature of neutrophil function in the cancer microenvironment with a specific emphasis on the mechanisms that regulate neutrophil mobilization, recruitment and activation.
Section
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Study Setting And Subjects
Details of study setting and subjects have been described . In brief, men randomized to the screening arm of the Prostate, Lung, Colorectal and Ovarian Trial were eligible for this nested casecontrol study, if they had at least one valid screening for prostate cancer , before 1 October 2001 , completed the baseline risk factor questionnaire, provided a blood sample and signed the informed consent for etiologic studies of cancer . All men were followed from their initial valid prostate cancer screen , to first occurrence of prostate cancer, loss-to-follow-up, death or 1 October 2001, whichever came first.
The eligible group included 1320 prostate cancer cases . For comparison, we selected 1842 controls using risk-set sampling, frequency matched to cases by age , ethnicity , time since initial screening and year of blood draw .
Sylvester Researchers Show Nitric Oxide Suppresses Drug
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Researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown in animal models that S-nitrosoglutathione , a compound that increases nitric oxide levels, suppresses castration-resistant prostate cancer and has a major impact on tumor microenvironments. The discovery could lead to new therapies for prostate cancer patients with few options. The study was published in the journal Proceedings of the National Academy of Sciences.
By using the nitric oxide donor GSNO, we increased nitric oxide levels and suppressed the growth of this particular type of prostate cancer, said Ranjith Ramasamy, M.D., assistant professor in the Department of Urology and senior author of the manuscript.
But even more important, the tumors did not develop further resistance that commonly occurs with most therapies currently available for prostate cancer, said Himanshu Arora, Ph.D., a researcher in the Department of Urology and first author of the manuscript.
Men with prostate cancer are often given androgen deprivation therapy, which blocks hormones that drive cancer growth. Unfortunately, tumors evolve over time, increasing the number of androgen receptors and adopting other mechanisms to resist this treatment.
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Nitric Oxide Exposure Induces Prostate Cancer Carcinogenesis And Pro
Prostate cancer is a leading cause of cancer death in men. Inflammation and overexpression of inducible nitric oxide synthase have been implicated in prostate carcinogenesis. A study explored the idea the hypothesis that nitric oxide NO exerts pro-tumorigenic effects on prostate cells at physiologically levels, and a pro-tumor secretory phenotype. The results were published in the journal Nitric Oxide.
In this study, the researchers analyzed the impact of acute exposure of normal prostate cells to NO, on prostate cancer cell proliferation and activation of DNA damage repair pathways. The investigators also assessed the long-term impact of chronic NO exposure on RWPE-1 cell migration.
According to the results, NO causes DNA damage through H2AX foci and p53 activation. This process leads G1/S phase block and activation of 53BP1 DNA damage repair protein, the researchers noted.
Long term adaption to NO results in increased migration and invasion potential, acquisition of anchorage independent growth and increased resistance to chemotherapy. This was recapitulated in PC3 and DU145 prostate cancer cells which upon chronic exposure to NO displayed increased cell migration, colony formation and increased resistance to chemotherapeutics. These findings indicate that NO may play a key role in the development of prostate cancer and the acquisition of an aggressive metastatic phenotype, the researchers concluded.
Nos And Male Reproductive System
The hypothalamic-pituitary axis plays core roles in reproduction and steroid hormone production in man. Gonadotropin-releasing hormone , also known as luteinizing hormone-releasing hormone , which is produced and secreted by the arcuate nucleus of the hypothalamus, could stimulate the anterior pituitary to episodically release follicle-stimulating hormone and luteinizing hormone . LH stimulates the Leydig cells to produce testosterone, and FSH exerts its effect directly on the Sertoli cells to promote spermatogenesis .
Figure 2.
Regulation of hypothalamic-pituitary axis. Abbreviations: LHRH, luteinizing hormone-releasing hormone GnRH, gonadotropin-releasing hormone LH, luteinizing hormone FSH, follicle-stimulating hormone.
In vitro studies have shown that NO stimulates LHRH secretion from the hypothalamus and modulates LH release from the pituitary . Ceccatelli reported that sodium nitroprusside, a NO donor, suppressed GnRH-stimulated LH release from pituitaries in male rats. Chatterjee et al. showed that NOS inhibitor p-nitro-L-arginine methyl ester enhanced GnRH-induced LH release from pituitaries in rats. Decreased level of GnRH and gonadotropin in chronic NO deficiency rats were also observed .
3.1.1. Testis
3.1.1.1. Testicular microcirculation
3.1.1.2. Leydig cells
3.1.1.3. Sertoli cells
3.1.1.4. Epididymis
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