The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention
Huzefa Vahora,1
Munawwar Ali Khan,2
Usama Alalami,2 and
Arif Hussain1
This article has been
cited by other articles in PMC.
Abstract
Nitric oxide (NO) in general plays a beneficial physiological role as a vasorelaxant and the role of NO is decided by its concentration present in physiological environments. NO either facilitates cancer-promoting characters or
act as an anti-cancer agent. The dilemma in this regard still remains unanswered. This review summarizes the recent information on NO and its role in carcinogenesis and tumor progression, as well as dietary chemopreventive agents which have NO-modulating properties with safe cytotoxic profile. Understanding the molecular mechanisms and cross-talk modulating NO effect by these chemopreventive agents can allow us to develop better therapeutic strategies for cancer treatment.
INTRODUCTION
Nitric oxide (NO) is a multifunctional gaseous transmitter which is lipophilic, as well as one of the smallest molecules found in nature.
1–
3 A free radical in gaseous state functions as a messenger via cyclic GMP (cGMP).
1 It was identified as a vasoactive small molecule in the 1980s and its cardiovascular activities are significant in relation to its vasorelaxation function as well as anti-thrombotic and anti-inflammatory effects. As a gasotransmitter, it regulates many physiological functions in the body, including neurotransmission,
immune response,
and anti-pathogenic effect,
1–
3 although NO is quite unstable and possess a half-life of 1 to 5 seconds in vivo.
Under normal physiological conditions, NO is produced by three isoforms of nitric oxide synthase (NOS) (
Fig. 1), Neuronal NOS (nNOS/NOS1) and endothelial NOS (eNOS/NOS3) form the constitutive NOS category (cNOS), activating NO production for seconds to minutes in nanomolar concentrations. Contrastingly, the third isoform, inducible NOS (iNOS/NOS2), produces greater amounts of NO, reaching micromolar concentrations and lasting hours or days. cNOS members are dependent on the calcium ion concentrations for their activity, thus they are able to produce lower amounts of NO for shorter durations, in comparison to iNOS which is independent of the calcium ion concentration.
1–
3 NOS enzymes are dimeric in nature and two distinct catalytic domains, N-terminal oxygenase domain, and C-terminal reductase domain, are present on each monomer. The substrates binding to the N-terminal are Heme-5,6,7,8- tetrahydrobiopterin (BH4), L-arginine, and oxygen and the substrates binding to the C-terminal are NADPH, flavin mononucleotide, and flavin adenine dinucleotide.
1 NO production is catalyzed by NADPH and oxygen as cosubstrates of L-arginine in the presence of NOS. The process of NO synthesis takes place in two steps: (i) hydroxylation of L-arginine to N?-hydroxy-L-arginine by NOS and (ii) oxidation of N?-hydroxy-L-arginine to L-citrulline and NO. The unpaired electrons of NO impart its reactivity towards inorganic molecules (oxygen, superoxide, or transition metals), DNA structures, and prosthetic groups, thus portraying its extensive biological activity.
3
[URL=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819660/bin/jcp-21-001f1.jpg]View Image[/URL]
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Figure 1.
The pathway elucidating the production of nitric oxide (NO). NOS, NO synthase; NADP+, nicotinamide adenine dinucleotide phosphate; nNOS, neuronal NOS; iNOS, inducible NOS; eNOS, endothelial NOS.
The actions of NO are mainly mediated through cGMP-dependent manner as well as cGMP-independent manner. The heme component of soluble guanylyl cyclase is targeted by NO, which further undergoes coupling with c-GMP-dependent protein kinase G and phosphodiesterases as well as cyclic nucleotide gated channels. In circumstances where cGMP is not available, the actions of NO are carried out independent of cGMP at low concentrations mainly in three ways, (i) interaction with proteins containing transition metal, (ii) interaction with proteins without the attached NO group, and (iii) modulation of cell signaling by posttranslational modification, mainly by forming S-nitrosothiol (SNO), which is achieved by coupling of a nitroso species to a reactive thiol group in specific cysteine residues, namely, S-nitrosylation.
1–
3
Over many years, NO was considered to be oncogenic in nature. Evidence has shown that NO plays a variety of roles in various stages of carcinogenesis by damaging the DNA, activating oncogenes, regulating apoptosis and metastasis, and inhibiting enzymes for DNA repair and tumor suppressor genes. Pro-tumor effects of NO were linked to the expression of NO-producing enzymes in tumor progression.
2 NO also portrays anti-tumor effects by utilizing the immune defense mechanisms in animal models of various human cancers.1,
3
ROLE OF NITRIC OXIDE IN CANCER BIOLOGY
NO, a free radical and water-soluble gas produced endogenously, regulates quite a few essential biological processes.
4 Since a few decades, an interest in NO has been increased as a molecule involved in carcinogenesis and tumor progression. However, a controversial facet exists in understanding its role in the biology of cancer.
4 This small molecule possesses the quality to either induce cancer progression or halt cancer growth and act as therapeutic agents.
4,
5 In conditions where NO is at lower concentrations, it aids in angiogenesis, which stimulates tumor progression by giving blood flow access to the tumor and subsequently result in cell proliferation (
Fig. 2).
5 On the contrary, higher levels of NO tend to be cytotoxic to cancer cells. This is achieved by the formation of peroxynitrite, which acts as an inducer of apoptosis and other toxic species during immune surveillances.5 Interestingly, peroxynitrite plays a dual role by aiding in inflammation-related carcinogenesis through the formation of 8-nitroguanine, a DNA-damaging entity and biomarkers.
3–
7
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819660/
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https://www.youtube.com/watch?v=wV_EaHHO5KU
[youtubeif]wV_EaHHO5KU[/youtubeif]
Pink Floyd - MADley - Mixed Collection (Audio)
Thanks trich.
Watched the video, and started my way through the studies.
(*Good tunes, as well. Thanks. And double points for Wishbone Ash!!!).
Being quite serious, the heart arrhythmia and humming, reminded me of holding the breath to balance hiccups. Different folks have had different perceptions of this intervention, but I have thought or understood the science therein, if there is science behind it, there is the probability or possibility that the holding of the breath helps to balance the CO2 and oxygen in the body/lungs better??
With the heart issues she addresses, that makes sense to me, at least preliminarily.
I'll finish reading the studies, and see what they say about NO helping to stop cancer progression.
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I met with the 3rd clinic's Doc today. She was very patient and personable.
I was a bit surprised to find out that, despite the ~2-month delay re scheduling to see her via Zoom, she is not the person who would likely be operating on me, and she had limited knowledge of the radio-oncology questions I have.
That said, she had no problem acknowledging that she was limited in knowledge in that regard, and also stated that the specificity of my questions, having come this far through the consultation phase, means that the best persons to answer my questions, would likely be the gurus there, whom I had initially sent my records to; 2 surgeons.
It's honorable to say, "I don't know that, but I can find out," or, "I know who to ask." Life doesn't require that we all be Rembrandt in our fields. It would be impossible anyway..
So she is forwarding my current status to the radio-oncology Doc there and the urological surgeon Doc there, and believes I should hear back from them within the week.. to schedule another Zoom conference.
I felt good about the meeting, and hope that sense of decent 'being' from earlier, before the meeting during the meeting, and currently, post meeting, lasts, but like with the cancer outcomes, there are no real guarantees. we'll just have to ride this pony, and see how far she goes.
In any case, I'm on to the final answers, for the nitty gritty questions, and can hopefully choose between either these folks, or the others I have had more interaction with, when the time comes.. hopefully in the near future.
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Still no answers from the previous surgeon or the radio-oncologist, to whom I had sent several pieces of correspondence and messages. either they're THAT busy, or I'm not welcome there now. Or...????
The best of the best often don't have to go looking for patients. And it's not like cancer went on vacation, and isn't providing any more patients for them.
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Snowing here lightly to moderately most of the morning, and about -18 a while ago.
Pax 3 tracking says it's still just a label, and the shipping service is waiting for it...
I want an end to questions, a greater sense of certainty as to who is capable of doing what, and then make a decision, though I know if it's External Beam Radiation, with or without brachy seeds, I will be away from my family, home, and pups for over (at least) 38 days on the final stint, as I will not be seeking radiation tx in Fairbanks, and likely not in Anchorage either.
Fortunately for me, no matter which tx option, I've always viewed Seattle as a pretty cool city, as cities go. Very cool, even. And if it's radiation instead of surgery, I'll damned near be a resident by the time the dust settles.
Edit: in an effort to help me with anxiety and so forth, during any extended or moderate absences from my home, family and pups, my wife has proposed obtaining a lap top or similar (with a remote mouse, I hope, as I HATE the tiny little control board on them), for me to travel with, so we can visually AND audibly connect, and they can take me for tours in the house, visit with the pups, plants in the shop, etc. My wife is pretty cool, very stressed, and still running her office from home. There are some circumstances and relationships in which I have been so fucking fortunate!!
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Valdy
(*Canadian music from the 1970s. He hung out for a bit at the Hippie School in Carcross, Yukon Territory Canada, at 1 point. He once made a music video of himself, hitch-hiking to his own concert back then. He and Bruce Cockburn played Fall of 1977 at the Farago Folk Festival, in the now-defunct mining town of Faro, Yukon Territory, back when Faro had money (and a population). You can find dirt-cheap real estate in Faro, Yukon these days, by the way.. ;^>) ).
'A Good Song'
https://www.youtube.com/watch?v=CVhb4KFO6nk&list=PLbMggkfLCxd4rJHbYpVT2Je_93KXmmRHr&index=2
'Simple Life' ('Ode to L.A.)
https://www.youtube.com/watch?v=mYVvYYRBC7s&list=PLbMggkfLCxd4rJHbYpVT2Je_93KXmmRHr&index=3
