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.
The Researchers Used This Group To Compare The Results From The Two Groups
They could see what was going on that was different between the prostate cancer and the non-prostate cancer groups.
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And they dont always tell the truth.
Detection Of Inos And Nitrotyrosine In Prostate Cancer Biopsies
Expression of iNOS protein has now been analysed in biopsies of more than 200 prostate cancer patients and was found to be expressed in prostate tumor cells in 80100% of these patients . Despite these reports no data about iNOS activity in prostate cancer are available. To investigate this we first analysed tissue samples from five different prostate tumor patients by immunohistochemistry for the presence of iNOS. None of these patients was under anti-androgen treatment at the time the biopsy was taken. Expression of iNOS was found in all tumors analysed , but expression levels varied among the different tumors. Similar to published findings , iNOS staining was predominantly found in tumor cells and occasionally in basal cells and secretory epithelial cells of benign prostatic glands. In parallel we analysed the prostatic tumor samples for the presence of nitrotyrosine, a post-translational protein modification, as a measure for iNOS activity . Interestingly, iNOS expression intensities as well as iNOS expression patterns strongly paralleled nitrotyrosine staining . Immunohistochemical stainings for iNOS and nitrotyrosine were specific, as evidenced by negative control reactions, in which the respective primary antibodies were omitted . Our results indicate that iNOS expressed in human prostate cancer is fully active and induces nitrosative stress.
Figure 1
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Insulin Resistance In Prostate Cancer Patients And Predisposing Them To Acute Ischemic Heart Disease
Correspondence:Correspondence:Correspondence:
Udayan Ray, Sarbashri Bank, Madawa;W. Jayawardana, Jahar Bhowmik, Frank Redwig, Pradipta Jana, Suman Bhattacharya, Emili Manna, Subrata Kumar;De, Smarajit Maiti, Philip Roberts-Thomson, Venkat Parameswaran, Asru;K. Sinha; Insulin resistance in prostate cancer patients and predisposing them to acute ischemic heart disease. Biosci Rep 31 July 2019; 39 : BSR20182313. doi:
No And Angiogenesis In The Tme
Angiogenesis occurs in hypoxic core regions of the tumor due to lack of oxygen and nutrients, which may be intricately regulated by the presence of NO. Hypoxia-inducible factor 1 and 2 activate the expression of pro-angiogenic growth factors such as VEGF, FGF-2, IL-8, PDGF, IGF2, and TGFβ. HIF1α and HIF1β are usually degraded in normoxic conditions, but are stabilized in hypoxic conditions as well as by low levels of NO and reactive nitrogen species . Low levels of NO may also regulate endothelial cell fate by activating GC and increasing cGMP levels , which acts directly on the endothelium to cause its reorganization into vessel-like formations . Additionally, low levels of NO are able to activate matrix metalloproteinases , which degrade the components of the extracellular matrix and paves the way for tumor cell dissemination outside of the tumor and endothelial cells into the tumor core for blood vessel formation . Thus, low NO is beneficial for ensuring upregulation of pro-angiogenic factors.
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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.
Roles of NO in prostate cancer. Abbreviation: NO, nitric oxide.
No Regulation By Arginine Metabolism
Although the physiological intracellular concentrations of arginine far exceed those required for eNOS to synthesize NO, the acute provision of exogenous arginine increases NO production . This phenomenon is known as the arginine paradox. The arginine pool derives from several sources, including dietary intake, body protein breakdown and endogenous de novo synthesis . Endogenous, systemic arginine production occurs through the intestinal-renal axis, in which citrulline produced by the intestine is converted into arginine by the kidneys. Here, citrulline availability is the limiting factor for the amount of arginine synthesized . To supply tissues with their required arginine needs, circulating arginine traverses cell membranes via the Na+-independent, cationic amino acid transport system y+, which regulates the availability of arginine for arginine-dependent synthetic pathways . Of note, arginine is also produced as an intermediate in the liver urea cycle, but here it participates in the detoxification of excess nitrogen; as such, it is not secreted into the plasma and does not contribute to the body’s pool of arginine .
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No In Head And Neck Cancer
Oral squamous cell carcinoma is the sixth most common malignancy and a major cause of morbidity and mortality . The high incidence of oral cancer and oral pre-cancer has been linked with habits of tobacco chewing and smoking . It is reasonable to assume that components of tobacco, as initiators of inflammatory response, could be responsible for the generation of ROS/RNS that may lead to lipid peroxidation, enhanced NO products, and deranged antioxidant defense system in tobacco users . The damage to genes sustained by elevated ROS/RNS could be one of the mechanisms by which cancer arises in long-term tobacco abuse . Raised levels of NO2 and NO3 were noted in patients with oral pre-cancer and in healthy individuals with tobacco habit . This indicates potential of nitrosative injury in tobacco users and,therefore, NO may have clinical relevance as a biomarker of inflammation and estimation of cancer risk in pre-cancer patients or in healthy tobacco users.
HPV, NO and head and neck cancer
Does Arginine Work For Cancer
Some researchers have exploited this cancer cell arginine requirement as an antineoplastic therapy to selectively starve tumors. Arginine deiminase , an arginine-metabolizing enzyme isolated from Mycoplasma, can inhibit tumor cell growth in culture and in animal tumor models.1 oct. 2004
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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.
Determination Of Psa In Supernatants Of Lncap Cells
LNCaP cells were seeded into 24-well plates and allowed to adhere for 24h in RPMI-1640/10% FBS medium. After an additional incubation period of 12h in RPMI-1640/10% cFBS 10nM R1881 was added with increasing concentrations of DETA/NO. After 24h PSA was assessed in the supernatants by enzyme immunosorbent assay . PSA levels were normalized according to cell numbers using a Neubauer chamber.
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Alterations Of Tumor Microenvironment By Nitric Oxide Impedes Castration
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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 .
Nup153 Is Part Of A Multimeric Complex Induced Upon Estrogen Stimulation
We previously demonstrated that eNOS nuclear import, followed by the formation of transcriptional complexes with ER, occurs in PCa cells under basal condition and is enhanced under estrogen stimulus . To understand whether and how Nup153 may take part of this activation pathway we investigated the possible formation of protein complexes potentially important for both eNOS nuclear translocation and its activation for transcriptional activity. We analysed the cells either in basal condition or after estrogenic deprivation followed or not by E2 treatment for 3h and 45min and/or 24h . Confocal microscopy analysis revealed co-localization of eNOS and Nup153 predominantly in PCa cells in basal condition . Quantification of double-labelled areas in BPH or PCa cells was 2% vs. 38%, respectively . Co-IP for eNOS confirmed an interaction between Nup153 and eNOS that was stronger in tumor as compared to BPH cells used as normal control.
To explore further the role of Nup153 in the E2 signalling we analysed the expression of VEGF Type2 Receptor , an E2-target gene, after Nup153 silencing and under hormone stimulation. Nup153 depletion virtually abrogated VEGFR2/KDR E2-responsiveness thus confirming Nup153 transcriptional role in this context .
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Nup153 Regulates Cell Migration And Colony Formation In Prostate Cancer Cells
To investigate Nup153 potential contribution to the biology of prostate cancer two cellular models were adopted: human immortalized cell lines derived from freshly explanted prostate tumors obtained from patients with diagnosis of clinically localized disease and selected for the absence of hormonal neoadjuvant treatment before surgery and the metastatic prostate cancer cell line LNCaP. We first evaluated whether Nup153 silencing by siRNA could affect migration and clonogenic ability of prostate cancer cells.
A significant reduction of migration capacity as well proliferation was found in primary tumor-derived and metastatic PCa cells undergoing to Nup153 downregulation as shown by scratch test and colony formation assay . Nup153 silencing progressively reduced cell metabolic activity , in agreement with its essential role in cell viability and control of cell cycle .
When we analysed Nup153 expression by confocal microscopy we found that in the unstimulated conditions Nup153 protein level was higher in PCa cells as compared to Benign Prostate Hyperplasia cells . Nup153 knockdown has been previously linked to alteration of the nuclear lamin A in breast cancer cells . Interestingly, in PCa cells , that show increased level of Nup153, the organization of nuclear lamin A, was also altered and the nuclei showed irregular shapes with membrane invaginations and multiple lobes .
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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.
Selection Of Prostate Cancer Patients
The present study was based on a subset of patients drawn from a retrospective casecontrol study of prostate cancer patients who were seen at the Royal Hobart Hospital, Tasmania, Australia and Sinha Institute, India. Patients were eligible for the study if they met all of the following criteria: age > 40 years; have not taken any aspirin-like medicine at least 1 month before the blood withdrawal. Those patients were included who were initially diagnosed with cancer and before the commencement of their formal treatment/medication blood sample was collected. We were able to avoid the influence of other disease and any medications. So, no cancer medicine was taken by the patients previously and before starting the cancer treatment, blood sample was withdrawn from the prostate cancer patients. Patients were excluded if any of the following criteria were encountered: diabetics and on insulin, nitrates and non-steroidal anti-inflammatory medications , suffering from any life-threatening diseases; heart-failure and taking different kinds of medicines. A total of 27 prostate cancer patients was considered and a total of 25 healthy control subjects who were free from any type of disease complicacy and were not taking any kind of medicine since last 1 month, were included in the study.
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Oxygen Arginine & Cancer
Dr. Joe Prendergast explains that one of the basic reasons arginine would be helpful for cancer patients is its ability to safely deliver more oxygen to oxygen-deprived tissues in the body. The entire world of alternative medicine agrees that getting more oxygen to the tissues is going to be bad news for any and all cancer cells because they have given up normal respiration for fermentation. When acid levels are high and oxygen levels are low we find cancer flourishinga situation that orthodox oncology ignores.
Arginine opens up the veins and arteries to increase blood flow and volume, thus increasing oxygen to the cells. In my cancer protocol, we also have magnesium increasing oxygen-carrying capacity as it relaxes blood vessels and brings down blood pressure, and we have sodium bicarbonate that, as every athlete knows, also makes it easier to circulate oxygen, thus immediately increasing endurance.
The Nobel Prize in Physiology and Medicine was awarded in 1998 to Drs. Furchgott, Ignarro, and Murad for their discoveries concerning Nitric oxide as a signaling molecule in the cardiovascular system. NO-inducing cell-signaling events within the cell producing it and the diffusibility of NO to other cells have led to the discovery of many other physiological functions in many different types of cells, including cancer cells.