I'm trying to dig deeper into whether Nitric Oxide Patches would slow APC or not. I know that the one canadian study in 2011 had 16 of 17 patients slow or stabilize their PSA growth but could that be due to the timing of the NO usage, which was very soon after their recurrence? These two studies below, from 2014 and 2015 indicate that NO presence made the cancer become more resistance, mutated and became more aggressive. You'll notice however, that they used naturally produce NO vs NO inhibitor samples. It sounds like they didn't provide external NO, like some of the men on this website use. "It should be stressed that in identifying iNOS/NO involvement in these photostress responses, we focused almost exclusively on natural intracellular iNOS/NO as opposed to exogenous NO or transfected iNOS employed in many other recent studies dealing with NO’s tumor-supporting properties."
Anyone care to provide their thoughts on these studies and whether or not they show some evidence of Nitric Oxide patch being risky to use, or is where these studies done in a way that are so different from using NO injection or patch delivery, that they don't have any relevance to using an NO patch in an attempt to slow APC PSA growth?
1. 2015 study:
ncbi.nlm.nih.gov/pmc/articl...
ACCELERATED MIGRATION AND INVASION OF PROSTATE CANCER CELLS AFTER A PHOTODYNAMIC THERAPY-LIKE CHALLENGE: ROLE OF NITRIC OXIDE
In summary, PC3 and DU145 cells that survived a PDT-like challenge were found to be more aggressive in terms of accelerated proliferation, migration, and invasion. This transformation was accompanied by greater activation or decreased/increased expression of key regulatory proteins such as MMP-9, TIMP-1, and α6 integrin. It should be stressed that in identifying iNOS/NO involvement in these photostress responses, we focused almost exclusively on natural intracellular iNOS/NO as opposed to exogenous NO or transfected iNOS employed in many other recent studies dealing with NO’s tumor-supporting properties. Thus, our findings are more realistic with regard to iNOS/NO involvement, particularly in the context of PDT as an anti-tumor modality. That conventional PDT (including ALA-PDT) for prostate and other malignancies might promote NO-dependent residual tumor aggressiveness is an alarming prospect, and suggests that iNOS inhibitors should be seriously considered as pharmacologic PDT adjuvants. At least two such inhibitors have the advantage of having already been tested in clinical trials, albeit unrelated to cancer or PDT [44,45].
iNOS is strongly induced in ALA-PDT-stressed prostate cancer PC3 and DU145 cells.
Photostress stimulates growth, migration and invasion of surviving cells.
iNOS inhibition or NO scavenging suppresses stimulated growth, migration and invasion.
Enhanced cell aggressiveness can compromise clinical PDT effectiveness.
iNOS inhibitors are proposed as pharmacologic PDT adjuvants.
2. 2014 study:
ncbi.nlm.nih.gov/pmc/articl...
Pro-Survival and Pro-Growth Effects of Stress-Induced Nitric Oxide in a Prostate Cancer Photodynamic Therapy Model
In summary, we have shown for the first time that prostate PC-3 cancer cells respond promptly to PDT-like stress by upregulating NOS2/NO, which enhances apoptotic resistance and stimulates proliferation. Yet to be investigated is whether stressed PC-3 cells use additional cytoprotective strategies, e.g. induction of cyclooxygenase-2 [44], and if so, their importance relative to NOS2/NO. Our finding that photostress-surviving cells used NO to proliferate more rapidly than controls is entirely novel in the context of PDT. If occurring in cancer patients, this response, along with hyperresistance to apoptosis, could seriously undermine PDT effectiveness. One possible answer is rational pharmacologic intervention with a NOS2 inhibitor [45]. Tested for the first time in this study involving a prostate cancer-PDT model, GW274150 would be an excellent candidate, having already been tested in humans as an anti-inflammatory agent [14].
3. Here is a link from a 2021 paper funded by the NIH:
ncbi.nlm.nih.gov/pmc/articl...
5.3. Prostate Cancer
Prostate cancer is highly prevalent in men and has an age-adjusted incidence of 453.8 per 100,000 and is highest amongst those 65–74 [165]. Similar to other cancers, iNOS expression was also significantly increased in prostate adenocarcinoma when compared to healthy prostate tissue [166]. Furthermore, previous work demonstrated that iNOS expression was greatest amongst those with metastasis and high Gleason scores, and one meta-analysis found that tumor iNOS expression may serve prognostic value [167,168]. These findings are backed by clinical studies, which suggest greater nitrosative stress in those with prostate cancer as compared to benign prostatic hyperplasia (BPH) and controls [169]. However, eNOS also appears to be linked to prostate cancer, as some but not all studies have shown that genetic polymorphisms of iNOS and eNOS carry an increased risk of high Gleason score prostate cancer [170,171,172]. eNOS may in turn upregulate pleiotrophin (PTN), expression through ERK activity, increasing tumor and endothelial migration, laying the groundwork for metastatic disease [173]. Additionally, the eNOS complex can interact with the estrogen receptor to transcriptionally alter other important gene products, such as Glutathione transferase P1, which are correlated to disease pathogenesis [174].
Prostate cancer is often initially androgen-sensitive, which is useful in androgen deprivation therapy, and is often a first-line therapy for advanced and metastatic disease [175]. This advanced form of prostate cancer is termed castration-resistant (CRPC) and is associated with poor outcomes [176]. Previous studies have implicated NO as a potential mediator of androgen resistance by androgen receptor transcriptional suppression and direct androgen receptor inhibition, which were mediated by iNOS and eNOS, respectively [177,178]. iNOS induction may encourage tumor growth, as two studies from the same lab found that NO promotes survival and accelerates tumor growth after oxidative stress [179,180]. However, testosterone, an androgen, also increases NO concentration and survival of prostate cancer cells, suggesting that NO’s mechanism in androgen sensitivity and resistance remains elusive [1,2,181,182]. These androgen-specific mechanisms may interact with previously defined effects of NO on hypoxia-induced HIF-1a and tumor angiogenesis, compounding the effect of nitric oxide on prostate cancer [183].
Have a good weekend,
George
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