[1] Hypoxia (low oxygen).
On the face of it, when a tumor outgrows its blood supply, it should be at a severe disadvantage. However, when cells do not get the oxygen they need, they induce HIF1alpha (Hypoxia Inducible Factor 1alpha). When that happens, a PCa cell becomes almost impossible to kill with current therapies.
Unsubscribe from any site that preaches that oxygen will kill cancer. It does not. The cancer wants oxygen restored. A major function of HIF1alpha is to trigger the generation of VEGF (Vascular Endothelial Growth Factor) this is a growth factor for new blood vessels (angiogenesis.)
While cancer cells will survive very well under low oxygen (hypoxic) conditions, hypoxia has been thrust upon them by tumor growth - hypoxia appears not to be the preferred state of PCa.
So, having put aside theories misattributed to Nobelist Otto Warberg, we are left in a quandry. Should we give the tumor more oxygen, enabling it to comfortably grow as before, or should we concentrate on countering HIF1alpha? Until we have a drug that effectively inhibits HIF1alpha, restoring the oxygen supply might remove HIF1alpha from the picture.
There is much interest in getting oxygen to cancer cells, in the false hope of killing them. So there are various schemes on the internet that mostly sound crazy to me. One would not want free oxygen in circulation, of course. Oxygen in the blood is carried by hemoglobin in red blood cells. For most of us, RBCs passing through the lungs will be almost all oxygenated, although for men with low testosterone, the RBC count will be low, limiting total oxygen in circulation.
A simple way to get more oxygen to tumors, is to cause the blood vessels to be chronically dilated.
[2] Nitroglycerin
[2a] "For over 130 years, nitroglycerin has been used medically as a potent vasodilator (dilation of the vascular system) to treat heart conditions, such as angina pectoris and chronic heart failure. Though it was previously known that these beneficial effects are due to nitroglycerin being converted to nitric oxide, a potent venodilator, it was not until 2002 that the enzyme for this conversion was discovered to be mitochondrial aldehyde dehydrogenase."
"A few months before his death in 1896, Alfred Nobel was prescribed nitroglycerine for his heart condition, writing to a friend: "Isn't it the irony of fate that I have been prescribed nitro-glycerin, to be taken internally! They call it Trinitrin, so as not to scare the chemist and the public." [11] The medical establishment also used the name "glyceryl trinitrate" for the same reason."
In study [3.1d] the men received "low-dose glyceryl trinitrate (GTN)" - the same stuff Nobel was given 120 years ago.
[3] Studies.
There are only 14 PubMed hits for <cancer hypoxia nitroglycerine>, so this is not a mainstream topic. Only two of those studies are specific to PCa.
[3.1] (Queen's University, Kingston, Ontario, Canada - Charles H. Graham lab)
[3.1a] (2001)
"Hypoxia in tumors is associated with malignant progression, metastatic spread, and increased resistance to radiotherapy and chemotherapy. Molecular O2 is required for the cellular production of nitric oxide (NO) by the enzyme NO synthase (NOS), and NO may block components of the adaptive response to hypoxia. Hence, we hypothesized that hypoxia increases drug resistance in tumor cells by inhibiting endogenous NO production."
"Human breast carcinoma ... and mouse melanoma ... cells were pre-exposed to 20% O2, 5% O2, or 1% O2, ..." etc, etc.
"Incubation of ... tumor cells in 1% O2 maximally increased their resistance to doxorubicin and 5-fluorouracil by 8.5-fold ... and 2.3-fold .., respectively, compared with incubation in 20% O2."
"... replacement of NO activity by use of the NO-mimetic glyceryl trinitrate (GTN) and diethylenetriamine NO adduct produced statistically significant attenuations in the development of resistance of 59% ... and 40% .., respectively"
"NO mediates chemosensitivity in tumor cells, and hypoxia-induced drug resistance appears to result, in part, from downstream suppression of endogenous NO production. These results raise the possibility that administration of small doses of NO mimetics could be used as an adjuvant in chemotherapy."
[3.1b] (2003)
"Tumor hypoxia has been correlated with metastasis and resistance to chemotherapy. Hypoxia is also associated with human prostate cancers, which are highly resistant to chemotherapy. We hypothesized that hypoxia contributes to chemoresistance in prostate cancer cells and this hypoxia induced chemoresistance can be inhibited by low concentrations of nitric oxide (NO) mimetics."
"Human PC-3 and mouse TRAMP-C2 prostatic adenocarcinoma cells were incubated in 20% or 0.5% O(2) for 12 hours with or without glyceryl trinitrate (GTN) (0.1 nM). This treatment was followed by a 1-hour incubation with doxorubicin ..."
"Hypoxic pre-incubation of the 2 cell lines resulted in increased survival following exposure to doxorubicin. Co-incubation of PC-3 and TRAMP-C2 cells with GTN (0.1 nM) inhibited the hypoxia induced resistance to doxorubicin."
[3.c] (2007)
"Hypoxia contributes to drug resistance in solid cancers, and studies have revealed that low concentrations of nitric oxide (NO) mimetics attenuate hypoxia-induced drug resistance in tumor cells in vitro."
"Low concentrations of the NO mimetics glyceryl trinitrate (GTN) and isosorbide dinitrate attenuated hypoxia-induced resistance to doxorubicin and paclitaxel."
"Compared with mice treated with doxorubicin alone, tumor growth was decreased in mice treated with doxorubicin and a transdermal GTN patch."
"There is evidence that the tumor microenvironment plays a significant role in determining the sensitivity of cancer cells to chemotherapeutic agents. For example, glucose deprivation has been shown to induce chemoresistance in Chinese hamster cells and human colon and ovarian cell lines. Similarly, changes in the pH of the tumor microenvironment lead to alterations in cell membrane permeability, which in turn can affect the ability of chemotherapeutic drugs to enter the cell. There is also evidence that, independently of changes in pH, tumor hypoxia decreases the efficacy of chemotherapy against solid cancers. One explanation for the lack of cytotoxicity toward hypoxic tumor cells is that many conventional anticancer drugs require oxygen for maximal activity. However, regardless of the oxygen requirements for maximal drug action, studies have shown that transient exposure of cells to hypoxia alters their phenotype so that they increase their intrinsic resistance to chemotherapeutic agents. Hypoxia inducible factor-1 is a transcriptional activator of many oxygen-regulated genes and has recently been implicated in hypoxia-induced resistance to chemotherapeutic agents. Although the nature of hypoxia-induced drug resistance is still poorly understood, it is likely that the participation of hypoxia inducible factor–dependent and –independent genes is required."
[3.1d] (2009) This is the important (human) study.
"A prospective, open-label clinical trial of men with an increasing prostate-specific antigen (PSA) level after surgery or radiotherapy was conducted. Men with PSA recurrence were enrolled in a 24-month trial investigating the effect of a low-dose, slow-release transdermal GTN patch. The PSA doubling time (PSADT) was compared before and after treatment initiation, as well as with a matched control group that received no immediate treatment for their PSA recurrence."
"A total of 29 patients were enrolled in the study. Of the 29 patients, 62% completed the 24-month protocol, with 10% experiencing clinical disease progression. The calculated PSADT of the treatment group before initiating GTN was 13.3 months, not significantly different from that of the matched control group at 12.8 months. In an intention-to-treat analysis, the end-of-study PSADT for the treatment group was significantly different at 31.8 months"
"We report the first clinical trial of a GTN patch in patients with prostate cancer. The prolongation of the PSADT and the safety of the drug, coupled with the corresponding preclinical in vitro and in vivo data documenting the ability of nitric oxide to attenuate hypoxia-induced progression of prostate cancer, warrant further testing in a placebo-controlled study."
[3.2] (Kyoto University Hospital,, Kyoto, Japan - H. Yasuda)
[3.2a] (2006)
"Nitroglycerin may improve the response to chemotherapy in advanced non-small cell lung cancer. The effects and mechanisms of nitroglycerin on the enhancement of chemosensitivity to docetaxel and carboplatin regimen (DCb) in patients with lung adenocarcinoma have not been reported."
"Seventeen patients with operable lung adenocarcinoma and stable angina pectoris were selected to investigate the effects of nitroglycerin on immunoreactivity for hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), P-glycoprotein (P-gp), the production of which is regulated by HIF-1 ..."
"Eight of 17 patients were treated with nitroglycerin patches before operation, but 9 of 17 patients were not."
"The rates of immunoreactive cells for HIF-1alpha, VEGF, and P-gp in tumor tissues treated with nitroglycerin were lower than those without nitroglycerin"
"Furthermore, the rates of immunoreactive cells for VEGF and P-gp proteins were significantly associated with those for HIF-1alpha in tumor tissue. The magnitude of decrease in plasma VEGF levels after treatment with nitroglycerin was significantly associated with response to DCb in patients with advanced lung adenocarcinoma."
[3.2b] (2008) Very good summary.
[3.3] (2015 - U.S. / Belgium)
"Nitroglycerin (NTG), a drug that has been in clinical use for more than a century, has a range of actions which make it of particular interest in an oncological setting. It is generally accepted that the main mechanism of action of NTG is via the production of nitric oxide (NO), which improves cardiac oxygenation via multiple mechanisms including improved blood flow (vasodilation), decreased platelet aggregation, increased erythrocyte O2 release and decreased mitochondrial utilization of oxygen. Its vasoactive properties mean that it has the potential to exploit more fully the enhanced permeability and retention effect in delivering anti-cancer drugs to tumour tissues. Moreover NTG can reduce HIF-1α levels in hypoxic tumour tissues and this may have anti-angiogenic, pro-apoptotic and anti-efflux effects. Additionally NTG may enhance anti-tumour immunity."
"While there is evidence of a positive action as a monotherapy in prostate cancer, there are mixed results in NSCLC where initially positive results have yet to be fully replicated. Based on the evidence presented, a case is made that further exploration of the clinical benefits that may accrue to cancer patients is warranted. Additionally, it is proposed that NTG may synergise with a number of other drugs, including other repurposed drugs, and these are discussed in the supplementary material appended to this paper."
...
I have been using a 0.1 mg / hour transdermal patch for only one month. I am not suggesting that anyone do the same. For one thing, it's way too soon to say how my PSA is being affected, if at all.
Side Effects: There was the anticipated head issue for a couple of days. Not a headache - more like a too much caffeine head.
"Experts recommend that the patches be removed at night, allowing the body a few hours to restore its responsiveness to nitrates." [2a]
-Patrick
[2a] en.wikipedia.org/wiki/Nitro...
[3.1a] jnci.oxfordjournals.org/con...
[3.1b] ncbi.nlm.nih.gov/pubmed/129...
[3.1c] clincancerres.aacrjournals....
[3.1d] ncbi.nlm.nih.gov/pubmed/194...
[3.2a] clincancerres.aacrjournals....
