Nitric-Oxide-Donating NSAIDs.

[pjoshea13]

New study below [1].

Seems an age since I last read about nitric-oxide-donating NSAIDs & a possible anti-cancer effect.

First: is anyone using one?

From a 2005 paper on a nitric-oxide-donating aspirin [2]:

"Nitric-oxide-donating aspirin (NO-ASA), consisting of ASA (aspirin) plus an -ONO2 moiety linked to it via a molecular spacer, is a new drug for cancer prevention. NO-ASA seems to overcome the low potency and toxicity of traditional ASA. The -ONO2 moiety is responsible for releasing NO, and it appears to be required for biological activity. In studies in vitro, NO-ASA inhibits the growth of colon, pancreatic, prostate, lung, skin, leukaemia and breast cancer cells, and is up to 6000-fold more potent than traditional ASA."

Fourteen years later & we have another NO-aspirin cell study [1]:

"Non-steroidal anti-inflammatory drugs (NSAID) have shown promise as anticancer agents by inducing cell death apart from their antipyretic, anti-inflammatory and anti-thrombogenic effects. In our current study, we investigated the oxidative stress mediated cell death mechanism of a NSAID derivative NCX4040 (a nitric oxide releasing form of aspirin) in castration-resistant prostate cancer (CRPC) PC3 cell line. Our data revealed that NCX4040 is more potent than its parent compound aspirin or nitric oxide (NO) releasing compound DETA NONOate. NCX4040 significantly induced hydrogen peroxide formation with ensuing oxidative stress and mitochondrial depolarization resulting in lipid peroxidation, cell cycle arrest, inhibition of colony growth and induction of apoptosis in PC3 cells. Moreover, NCX4040 inhibited migration potential of PC3 cells ..."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/314...

[2] ncbi.nlm.nih.gov/pubmed/160...

[Garp41]

Patrick,

Is this aspirin available to buy?

Doug

[pjoshea13 in reply to Garp41]

Doug,

The years fly by & I assumed that some NO-NSAIDs must have been approved by now. After all, they are supposed to be safer. But I don't see signs that the FDA has approved any. It didn't take this long for Zytiga & Xtandi!

I wonder if Nalakrats could throw together a NO-aspirin in his basement lab?

Apologies if I have raised hopes.

-Patrick

[Garp41 in reply to pjoshea13]

Patrick,

Since it's a safer aspirin, hard to believe it hasn't been approved..... criminal in my opinion, as I believe tens of thousands of people per year, at least, have bleeds from regular aspirin.

Doug

[cesanon in reply to Garp41]

Yes it is available to purchase:

tocris.com/products/ncx-404...

Description: NO-donating aspirin; anti-inflammatory and antitumor

Chemical Name: 2-(Acetyloxy)benzoic acid 4-[(nitrooxy)methyl]phenyl ester

Purity: ≥98% (HPLC)

Biological Activity

NO-donating aspirin; anti-inflammatory. Blocks inflammatory mediator production in isolated human monocytes (IC50 values are 0.07, 0.13, 0.15 and 0.18 μM for IL-1β, PGE2, IL-10 and TNF-α respectively). Decreases COX-2 expression (IC50 = 0.13 μM); disrupts proteasome-mediated degradation of iκB-α. Antiproliferative in HCT116 colon cancer cells; sensitizes drug-resistant ovarian tumor cells to cisplatin (Cat. No. 2251).

Product Data Sheet

documents.tocris.com/pdfs/t...

[Hidden in reply to cesanon]

That's some pricey stuff. It's not clear what dose an individual pill provides or how many pills you get when you order a particular amount, or is this in powder form?

[cesanon in reply to Hidden]

10mg pills of viagra are an alternative (relatively inexpensive in generic form)

l-argenine is an alternative

[TFBUNDY in reply to cesanon]

I use generic Cialis as a nitric oxide donor. Oh the side effects... oh Oh OH....

[PhilipSZacarias in reply to cesanon]

Tocris is a supplier of research grade chemicals and will not sell to individuals. This indicates that the drug has not been approved by the FDA. Maybe we should get into the drug manufacturing business Cheers, Phil

[Ralph1966]

I am using L-Arginine, 1000 mg twice daily, which ends up as Nitric-oxide.

Nalakrats also recommended this in a higher dose 1000 mg three times daily.

There is another explanation as L Arginine potentiate T cells in the immune system.

In 1991, the University of Minnesota conducted one of the first studies to use l-arginine combined with omega-3 fatty acids and RNA. The study included 20 patients ages 31-80 from the ICU.

The researchers gave 11 patients a supplementation of 12.5 grams of l-arginine, 1.25 grams of RNA, and 11.1 grams of omega-3 fatty acids. The other 9 patients received a placebo. Each received their supplement for 7-10 days.

Those who took the l-arginine supplement had increased growth of T-cells, which aid the immune system to fight off infection, and also cancer!

[tango65]

Thanks Patrick, very interesting.

[snoraste]

From WebMd:

"L-arginine also stimulates the release of growth hormone, insulin, and other substances in the body."

Need to do some cost-benefit analysis.

[TFBUNDY]

Do all nitric oxide releasing compounds like l-arginine and nitroglycerin have a Viagra like effect ;-)?

[pjoshea13 in reply to TFBUNDY]

Mayo:

"Taking oral L-arginine might improve sexual function in men with erectile dysfunction due to a physical cause."

"mayoclinic.org/drugs-supple...

Topical nitro has been used for ED - presumably at a much higher dose than the patch.

None of the above should be combined with Viagra, etc.

-Patrick

[TFBUNDY]

I just came across this which suggests (I think), that arginine supplement would be a bad idea. So much information....

karger.com/Article/FullText...

[pjoshea13]

Interesting find.

"Melanoma, hepatocellular carcinoma, and prostate carcinoma were most frequently deficient in ASS" (Argininosuccinate synthetase). [1]

Which suggests that PCa might respond well to arginine depletion via ADI-PEG 20.

There has been a "Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors" - including PCa. [2]

"ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted, and expansion cohorts are now accruing for both castrate-resistant prostate cancer and non–small cell lung cancer at a recommended phase II dose of 36 mg/m2."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/147...

[2] clincancerres.aacrjournals....

[TFBUNDY]

To arginine or not to arginine? That is the question.... Not, in my view....