Nobel Prize - William Kaelin, Peter Ratcliffe, and Gregg Semenza.

[pjoshea13]

I was interested to see this morning's news [1] because it has a bearing on a point I was recently trying to make (unsuccessfully).

It's not uncommon to find someone on a cancer site claim that cancer hates oxygen. 'If only we could get more oxygen to the cancer it would die.' PCa is not at all inconvenienced by a robust supply of oxygenated blood. However, solid tumors are eventually victims of their success & become "hypoxic" (low oxygen) due to a blood supply that has been outgrown.

The response to hypoxia is multifactorial (all related to cell survival), but the hallmark of the response is the building of new blood vessels.

Kaelin was co-author of a 2000 Dana-Farber paper [2]:

"Chronic hypoxia, a hallmark of many tumors, is associated with angiogenesis and tumor progression. Strategies to treat tumors have been developed in which tumor cells are targeted with drugs or gene-therapy vectors specifically activated under hypoxic conditions."

Semenza (2009) [5]:

"In cancer, vascularization is required for tumors to grow beyond microscopic size, a process that involves HIF-1-dependent production of angiogenic growth factors. Daily treatment of prostate cancer xenograft-bearing mice with low-dose anthracycline (doxorubicin or daunorubicin) chemotherapy inhibits HIF-1 DNA-binding activity, HIF-1-dependent expression of angiogenic growth factors, mobilization of circulating angiogenic cells, and tumor vascularization, thereby arresting tumor growth."

Hypoxia-inducible factor-1alpha [HIF1a] causes the generation of vascular endothelial growth factor [VEGF]. From a 2014 Spanish paper:

"Induction of angiogenesis represents one of the major hallmarks of cancer. The growth of new vessels is crucial to provide malignant cells with an adequate supply of oxygen and nutrients. It is generally accepted that vascular endothelial growth factor (VEGF) is a major driver of the angiogenic process in physiological and pathological processes in both embryo and adult. VEGF is often found overexpressed in tumors, as well as its receptors VEGFR1 and VEGFR2. Hence, several different strategies have been designed to target VEGF signal transduction. In the last decades, multiple inhibitors have been therapeutically validated in preclinical models and several clinical trials. Neutralizing monoclonal antibodies against VEGF and small molecule tyrosine kinase inhibitors targeting VEGFRs have been shown to block its angiogenic activity, resulting in tumor vascular regression, anti-tumor effects and improvements in patient survival. However, side effects and lack of efficacy in some instances challenge the potential clinical impact of these therapies. This review examines the role of VEGF signaling in cancer and outlines the current status of anti-angiogenic therapies against VEGF pathway."

In 2002, Kaelin described "How oxygen makes its presence felt" [3].

From 2011 [4]:

"When cells are placed in a low oxygen environment they normally undergo a series of metabolic adaptations including an increase in glucose uptake and glycolysis and a decrease in oxidative phosphorylation. Conversely, the presence of oxygen is associated with a decrease in glycolysis and an increase in oxidative phosphorylation. The coupling of oxidative phosphorylation is known as the Pasteur Effect and is mediated by the HIF transcription factor."

"HIF is a heterodimer consisting of an unstable alpha subunit and a stable beta subunit (also frequently called ARNT) (Kaelin and Ratcliffe 2008). Under low oxygen conditions the HIF alpha subunit is stabilized, dimerizes with a HIF beta subunit, translocates to the nucleus, and transcriptionaly activates a suite of genes that increase glucose uptake, increase glycolysis, and decrease oxidative phosphorylation."

***

HIF1a is responsible not only for triggering angiogenesis, but also for cell survival genes that conribute to treatment resistance. In the presence of adequate oxygen, HIF1a becomes unstable & is eliminated.

Ironically, those who want to restore a good supply of oxygen to hypoxic tumors are on to a good thing. But for men with advanced PCa who are on ADT, the red blood cells that carry oxygen are much reduced. ADT accelerates hypoxia.

For men not on ADT, or on an ADT vacation, restoration of high-normal testosterone will restore normal RBC counts.

Possible strategies for increasing the oxygen supply (a) increase the re-oxygenation rate via exercise & (b) dilate blood vessels via a nitroglycerine patch.

-Patrick

[1] nytimes.com/2019/10/07/heal...

[2] ncbi.nlm.nih.gov/pubmed/239...

[3] genesdev.cshlp.org/content/...

[4] ncbi.nlm.nih.gov/pmc/articl...

[5] ncbi.nlm.nih.gov/pubmed/198...

[AlanMeyer]

I remember that, in the 1990's, there was quite a lot of excitement about the inhibition of angiogenesis as the cure for all cancers. We in the computer programming group at the National Cancer Institute wondered how much longer we were going to still be working there.

Alan

[dentaltwin in reply to AlanMeyer]

I remember this article (bet you do too) that caused a run on one stock (I'm guessing Entremed, if it was public at the time). Plenty of people plowed in at the top, only to see the price collapse by the end of the day.

nytimes.com/1998/05/03/us/h...

[cesces]

Dr. Myers had me on low dose Viagra. I believe his reasoning was to feed the prostate cancer enough oxygen so that it wouldn't vascularize.

[tom67inMA]

Exercise, exercise, exercise! I was just reading how it builds blood vessels into tumors and also releases NK "killer" cells. Those blood vessels help the NK cells (and for that matter, chemo and other drugs) get inside the tumor where they can do their job.

cell.com/trends/molecular-m...

[pjoshea13 in reply to tom67inMA]

Tom,

From the paper you cited:

"While increased tumor perfusion has been previously regarded as unfavorable, the benefits of increasing access of immune cells and antineoplastic drug delivery, in addition to resolving hypoxia-related intratumoral stress may, in the right setting, outweigh the disadvantage of providing more nutrient and oxygen to the tumors through perfusion."

15 years ago I wouldn't go anywhere arginine. How could nitric oxide be other than harmful?

But PCa is like living with pit bull. Keep it supplied with what it wants or it will turn on you. It's a paradox that I have taken to heart - don't provoke the cancer with aggressive treatment if you don't have a way of dealing with it's adaptations.

-Patrick

[tom67inMA in reply to pjoshea13]

Interesting, because aggressive treatment is what turned my former pit bull into one of those little poofy dogs that yap a lot, but generally isn't a danger in its current form. Someday it may turn into a hell hound, but for the moment I've got better quality of life than a year ago.

[rassusukumaran in reply to pjoshea13]

I acknowledge your logic. The problem seems to be to decide when and how to treat Ca non agressively. Its a fine line, although we understand the Darvinian dynamics involved in Ca mutation.

[snoraste]

Patrick,

How do you reconcile use of anti-oxidant supplements with this? I understand that healthy cells need antioxidants that we usually get thru diet, but adding supplements rich in antioxidants? your thoughts?

[pjoshea13 in reply to snoraste]

In the context of this post, oxygen is comparable to a nutrient that must be carried in the blood from lungs to tissue for cellular respiration. Free oxygen would be dangerous in circulation, but is safe when bound to hemoglobin in RBCs.

In the context of antioxidants, we start with the reduction-oxidation [Redox] reaction. Basically, this involves the transfer of electrons. The reduction entity loses electrons, whereas the oxidation entity gains them. During Redox, there is the danger of the generation of free radicals. This is where antioxidants in the diet are supposed to be protective & quench the pesky radicals.

Many cancer therapies rely on the generation of reactive oxidant species [ROS]. Antioxidants would neutralize ROS & should be avoided. However, at high levels, antioxidants can become pro-oxidant & might thus make therapy more effective. Supplements that have been found to be useful (at least in the lab) are invariable so because they support ROS.

& so, the idea that one can fight cancer via a diet "rich in antioxidants" is mistaken. Antioxidants must be taken at pro-oxidant doses (don't ask) - which means supplements.

-Patrick

[snoraste in reply to pjoshea13]

So if an antioxidant supplement is not hormetic, it should be avoided. It still leaves the question of regular intake of (dietary) antioxidant open. They also interfere with ROS agents, no? I'm having a hard time believing (out of personal bias, of course) that fruits and vegetables could be bad for PCa.

[pjoshea13 in reply to snoraste]

Fruits and vegetables are not bad for PCa, as such - they are potentially bad for cancer treatments that induce ROS.

-Patrick

[TFBUNDY in reply to pjoshea13]

There is a huge amount of knowledge here, but do we have any conclusions? WTF to do? Getting the Wrong Idea, or taking the right stuff in the wrong dose could accelerate the beast. I hope the science catches up fast before I kill myself. BTW I tried a nitric oxide pill and got a bit extra exercise. I hope the oxygen did me some good. Things are looking up

[Shanti1 in reply to snoraste]

Many nutrients that have been labeled "antioxidants" are actually phytochemicals that likely have their potential anti-cancer benefits (in those with cancer) due to mechanisms besides being antioxidants. For example, curcumin inhibits nf-kb, EGCG inhibits VEGF, Sulforaphane modulates the androgen receptor, quercetin helps eliminate senescent cells, etc. I am leary of straight "antioxidants" such as d-alpha-tocopherol or beta-carotene. Also would use the above nutrients with caution when undergoing a therapy that relies on oxidative stress and DNA damage as part of its "kill" method.

[pjoshea13 in reply to Shanti1]

I'll just add that all of the useful polyphenols seem to inhibit activation of NF-kB. It's fascinating that phytochemicals that evolved to protect specific plants from environmental insult, also have potential benefit to us.

About 14 years ago, I decided that NF-kB was the most logical target in PCa, since it is chronically activated & responsible for cell survival via multiple pathways. I came across a site that Dr. Tom Gilmore of the Gilmore lab, Boston U. had set up:

people.bu.edu/gilmore/nf-kb...

Looking at the list of inhibitors & supporting studies, it looks as though the last update was a decade ago, but it remains a valuable resource. I stick to inhibitors that are polyphenols:

people.bu.edu/gilmore/nf-kb...

-Patrick

[Shanti1]

Interesting post Patrick. I agree, the idea that cancer "hates" oxygen and can't grow in an oxygenated environment is one that isn't true and has been perpetrated across the internet. Interesting though, that keeping the supply of oxygen available in PC may have its benefits for drug delivery, sensitivity to radiation, and keeping it from becoming more aggressive. In the last thread on this topic, it was pointed out the prostate cancer likes a low oxygen environment, as evidenced by the areas it thrives in the body, yet PC tends to use oxidative phosphorylation over glycolysis until late stage, so it must have enough oxygen to do so, even in the areas of the bone, lymph and prostate gland itself.

Hyperbaric and ozone therapy are two oxygen therapies that are often employed to fight cancer. Although I don't think they do much as a monotherapy, they may have a role in increasing oxidative stress in combo with radiation and chemo. A burst of oxygen to a cancer cell that has been devoid of oxygen could cause ROS bursts that the cancer cell with its dysfunctional mitochondria and lessened internal antioxidant system would not be able to recover from.

[FRTHBST]

There also is a theory that at high enough doses, Vitamin C, eg given by IV, becomes an oxidant. This creates a peroxide reaction that normal cells can deal with while cancer cells lacking the caspase enzyme cannot.

prnewswire.com/news-release...

While this link is to a relatively small 2017 review study, the oxidative peroxide reaction is mentioned in other studies appearing in pubmed searches on cancer and Vitamin C.

[podsart in reply to FRTHBST]

Vitamin C seems to reappear periodically. A few times the strategy of using vitamin C with antibiotic? would be effective. Then no ensuing stories of its clinical success or further use clinically or by our community. Is part of problem that this uses cheap drugs and therefore not attractive to big Pharma?

[Shanti1 in reply to FRTHBST]

High dose vit C is thought to work as a pro-oxidant. I know there are some studies with IVC showing benefit for other cancer types, but unfortunately, IVC for CRPCa didn't show any benefit in this study: ncbi.nlm.nih.gov/pmc/articl.... Perhaps combined with other pro-oxidant therapies or combined with antibiotics (doxy and azithromycin are what have been looked at in cell studies) there would be a better response, but those taking this approach are working off theory.

[arete1105]

So I get the impression that anti angiogenesis is good for cancer by reducing blood vessels to the tumor. So I checked out supplements that feature anti angiogenesis and come up with this list:

Herbs and associated phytochemicals

Aloe barbadensis (aloe vera leaf and pulp extracts)

Angelica sinensis (aqueous extracts)

Artemisia annua (artemisinin)

Camellia sinensis (epigallocatechin)

Chrysobalanus icaco (methanol extract)

Curcuma longa (curcumin)

Dysoxylum binectariferum (flavopiridol)

Flos magnoliae (magnosalin)

Ganoderma lucidum (triterpenoids)

Ginkgo biloba (ginkgolide B)

Glycyrrhiza glabra (isoliquiritigenin,; glabridin)

Hibiscus sabdariffa L. (protocatechuic acid)

Livistona chinensis (aqueous extract from seed)

Matricaria chamomilla (flavonoids: apigenin, fisetin)

Ocimum sanctum (carnosol, ursolic acid)

Omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid)

Magnolia obovata (honokiol)

Panax ginseng (saponins: 20(R)- and 20(S)-ginsenoside-Rg3)

Polypodium leucotomos (difur)

Poria cocos (1–3-a-d-glucan)

Polygonum cuspidatum (resveratrol)

Proanthocyanidin

Quercetin

Rabdosia rubescens Hora (ponicidin and oridonin)

Rosmarinus officinalis (carnosol and ursolic acid)

Scutellaria baicalensis (baicalin and baicalein)

Silybum marianum (silymarin)

Soy isoflavones (genistein, daidzein)

Tanacetum parthenium L. (parthenolide)

Tabebuia avellanedae (ß-lapachone)

Taxus brevifolia (taxoids)

Viscum album (lectins)

Zingiber officinale (6-gingerol)

Other Chinese herbs (see Table VI)

Cyclo-oxygenase-2 antagonists (see Table IV)

Minerals

Selenium

Animal-derived

Bovine cartilage

Shark cartilage (water soluble extract AE-941)

Squalus acanthias (dogfish liver: squalamine)

Vitamin D (1a ,25-D3)

You will notice that at the top of the list is Aloe Barbadensis(AB). This is the product that Father Zago promotes in his book Cancer Can be Cured.

I have been taking, including the AB product, several products from that list since I was diagonised in 2013. My 3 nuclear and 5 MRIs all show "no evidence of osseous matastasis." No proof but a high correlation. I do have groin mets in the lymph nodes there.

[j-o-h-n]

With all of the above, Boy oh Boy do I miss whacking the bishop....

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 10/08/2019 5:25 PM DST