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Killing cancer stem cells (CSC) - depleting the NAD pool

nad cancer

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#1 midas

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Posted 24 November 2014 - 10:39 AM


Team discover that derivitive of vitamin B3 (Nicotinamide Riboside) prevents liver cancer in mice.

 

http://medicalxpress...=daily-nwletter


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#2 Bryan_S

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Posted 22 April 2015 - 11:00 PM

Oncoscience 2015, Vol.2, No.2

 

Oncogene-induced NAD+ depletion in tumorigenesis

 

http://www.impactjou...s/1/154/154.pdf

 

 

Wow . . . "Replenishing the NAD+ levels by nicotinamide riboside (NR), a derivative of vitamin B3, prevented and abolished DNA damage and aggressive tumor formation"

 

Again Wow . . . "NR seems therefore to be an efficient therapy for the treatment of various cancers in which predictive and prognostic factors can be identified as oncogeneassociated genotoxic stress. Clinical trials with NR for treatment of such cancers are under consideration. However, developing a methodological screen to find more efficient and stable NAD+ “boosters” and, understanding the mechanisms of NAD+ depletion-dependent DNA damage would offer a broad spectrum of new possibilities to decisively prevent and cure cancer in human beings. The development of drug discovery platform based on screening of new compounds that enable to abolish DNA damage by increasing NAD+ levels can thus be an exciting investment in the war against cancer."

 

Who is writing this stuff, are they being payed by ChromaDex who holds the patent to make this, either we are seeing a huge public ruse or this NAD+ precursor is for real! This stuff should be selling off the shelf.

 

"We have a DNA maintenance problem, cleanup on aisle 6."

1396914351697274.jpg


Edited by Bryan_S, 22 April 2015 - 11:04 PM.

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#3 midas

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Posted 23 April 2015 - 12:38 AM


Who is writing this stuff, are they being payed by ChromaDex who holds the patent to make this, either we are seeing a huge public ruse or this NAD+ precursor is for real! This stuff should be selling off the shelf.

 

 

Its looking pretty legitimate to me Bryan, the two guys named at the top of your link (Krishna S. Tummala and Nabil Djouder) have been working in this field for a long time and both work at The Spanish National Cancer Research Centre in Madrid, I would doubt they are tied to Chromadex in any way other than maybe Chromadex supplying the NR as they are the sole supplier of NR......

 

Krishna S. Tummala....Back in November last year... http://www.sciencedi...535610814003924

 

"Restoring NAD+ pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD+ can be prophylactic or therapeutic in HCC"

 

And Nabil Djouder working at the same Cancer Research Centre in Spain..

http://www.cnio.es/E...on.asp?pag=1251

 

This is all very, very, interesting.

 


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#4 warner

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Posted 27 October 2016 - 02:15 AM

Was wondering if Bryan (and others) could summarize what their thoughts are about NR and cancer.  I'm convinced by the science so far that NR is very likely to help prevent most forms of cancer, but less convinced that it will not accelerate the growth of existing cancers (such as undetected prostate, colon, breast, etc., cancers), or at least complicate the treatment of such cancers.  For example, is there research I'm not seeing that at least indicates that such cancers in non-human subjects are not accelerated by NR?  Thanks.

 

(btw, I'm aware of the good results with liver cancer, but what about the 10 or so other major age-related cancers?)

 

(I guess the success of nicotinamide with non-melanoma skin cancers is also likely good news for NR - in fact, my wife has recently switched from nicotinamide to NR for basal cell carcinoma prevention)


Edited by warner, 27 October 2016 - 02:30 AM.


#5 bluemoon

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Posted 27 October 2016 - 02:29 AM

David Sinclair has discussed the positive effect of NMN on mice with liver cancer, but I haven't read about NR on cancer. I realize that NR is similar to NMN but is it possible not close enough in this case?   



#6 warner

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Posted 27 October 2016 - 02:42 AM

David Sinclair has discussed the positive effect of NMN on mice with liver cancer, but I haven't read about NR on cancer. I realize that NR is similar to NMN but is it possible not close enough in this case?   

 

Positive effects of NR on liver cancer well-established.  This research, for example, describes how liver cancer was induced by lowering NAD+, and then reversing the effects with NR:

 

Derivative of vitamin b3 prevents liver cancer in mice

https://www.scienced...41120123234.htm



#7 warner

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Posted 28 October 2016 - 02:24 AM

Lots of confirmation there for what Brenner's group is finding.  They also wondered about cancer:

 

During the long-term NMN study in healthy mice, Imai also said they monitored the animals for any potential increase in cancer development as a result of NMN administration.  "Some tumor cells are known to have a higher capability to synthesize NAD, so we were concerned that giving NMN might increase cancer incidence," Imai said. "But we have not seen any differences in cancer rates between the groups."

 

Hmm... apparently no increase or decrease in cancer rates (haven't read the original paper yet).  Perhaps NR promotes as much cancer as it prevents (when administered for a lifetime).  Also still an open question of what the effect is on existing tumors/cancer in older animals newly exposed to high doses of NR.


Edited by warner, 28 October 2016 - 02:25 AM.


#8 Bryan_S

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Posted 28 October 2016 - 09:06 AM

 

Lots of confirmation there for what Brenner's group is finding.  They also wondered about cancer:

 

During the long-term NMN study in healthy mice, Imai also said they monitored the animals for any potential increase in cancer development as a result of NMN administration.  "Some tumor cells are known to have a higher capability to synthesize NAD, so we were concerned that giving NMN might increase cancer incidence," Imai said. "But we have not seen any differences in cancer rates between the groups."

 

Hmm... apparently no increase or decrease in cancer rates (haven't read the original paper yet).  Perhaps NR promotes as much cancer as it prevents (when administered for a lifetime).  Also still an open question of what the effect is on existing tumors/cancer in older animals newly exposed to high doses of NR.

 

 

We raised this issue on the thread ourselves earlier. As we raise NAD levels we also provide our PARP processes the energy source it needs. Also since A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer demonstrated a 23% reduction this was also a pointer NAD Repletion works. This was a human study and the aforementioned liver cancer study on mice also suggested the same.
 
Professor Shin-ichiro Imai is keeping an eye on this as I expect the other researchers are.

Edited by Bryan_S, 28 October 2016 - 09:07 AM.

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#9 warner

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Posted 28 October 2016 - 12:54 PM

 

 

Lots of confirmation there for what Brenner's group is finding.  They also wondered about cancer:

 

During the long-term NMN study in healthy mice, Imai also said they monitored the animals for any potential increase in cancer development as a result of NMN administration.  "Some tumor cells are known to have a higher capability to synthesize NAD, so we were concerned that giving NMN might increase cancer incidence," Imai said. "But we have not seen any differences in cancer rates between the groups."

 

Hmm... apparently no increase or decrease in cancer rates (haven't read the original paper yet).  Perhaps NR promotes as much cancer as it prevents (when administered for a lifetime).  Also still an open question of what the effect is on existing tumors/cancer in older animals newly exposed to high doses of NR.

 

 

We raised this issue on the thread ourselves earlier. As we raise NAD levels we also provide our PARP processes the energy source it needs. Also since A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer demonstrated a 23% reduction this was also a pointer NAD Repletion works. This was a human study and the aforementioned liver cancer study on mice also suggested the same.
 
Professor Shin-ichiro Imai is keeping an eye on this as I expect the other researchers are.

 

I'll get the Imai paper today and hopefully be able to determine if "no difference" in cancer rates means truly "no difference" or simply "not enough data" (i.e., too few cancer cases to tell us much).

 

I'm encouraged by the liver cancer results, but the skin cancer reduction with Nam is a bit ambiguous for NR, since the amounts of Nam used, on a molar basis, were much larger than our typical NR doses, and we also know that Nam is a sirtuin suppressor, etc., so it just depends on the exact mechanism of the skin cancer suppression, and how NR compares to Nam in that respect.

 

wrt cancer, NR supplementation may turn out to be something like (low dose) sex hormone replacement, where the benefits outweigh a smallish rise in cancer risk (as in low dose E2 replacement raising slightly ones risk of breast cancer, but providing a wide range of health benefits).  We'll see!



#10 warner

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Posted 28 October 2016 - 06:28 PM

In the Imai (Mills et al.) paper ( http://www.cell.com/...4131(16)30495-8 ) the only cancer-related observation made was wrt causes of death:  "No obvious differences were observed for the causes of death, which included urinary tract obstruction, thrombosis, and myocardial infarction, between control and NMN-administered mice."  So Imai's verbal comment simply meant they were happy to not see a lot of new cancer in the NMN mice, but the study was not really designed to answer the broader question of cancer prevention/promotion by NMN.

 

Attached File  causes of death.jpg   26.34KB   3 downloads


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#11 warner

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Posted 28 October 2016 - 10:32 PM

What I understand of it is that certain cancer cells have a higher sensitivity to NAD availability. So if you have cancer one way to kill cancer is to strip the body of NAD. The cancers cells which are more sensitive to NAD availability should then die first before the normal cells are impacted. So taking NR may counter act certain cancer drugs which aim to inhibit it.

Yup, that's the concern - that however much good NR may do in the absence of cancer, there may be risks to taking it in the presence of certain cancers, and we may not be aware of the existence of such cancers when first taking NR.  Even in that case, it might still make sense to take NR as a calculated risk, but the calculation is not possible without knowing a lot more about how various cancers interact with NR supplementation.

 

Personally, I'm taking the risk that the benefits of NR will outweigh such cancer risks (if any), but, as with the researchers in the latest study, we anxiously await further data.  :unsure:


Edited by warner, 28 October 2016 - 10:34 PM.


#12 Bryan_S

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Posted 06 December 2016 - 03:23 PM

Pathway linked to slower aging also fuels brain cancer

http://medicalxpress...ging-fuels.html


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#13 Nate-2004

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Posted 06 December 2016 - 04:07 PM

Pathway linked to slower aging also fuels brain cancer

http://medicalxpress...ging-fuels.html

 

That's terrible. Hopefully none of us have existing tumors. I assume it's fine if you don't. I don't have a history of that kind of cancer in my family.



#14 midas

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Posted 06 December 2016 - 05:02 PM

 

Pathway linked to slower aging also fuels brain cancer

http://medicalxpress...ging-fuels.html

 

That's terrible. Hopefully none of us have existing tumors. I assume it's fine if you don't. I don't have a history of that kind of cancer in my family.

 

Scientists Find Promising New Approach to Preventing Progression of Breast Cancer

https://www.scripps....25/felding.html

"To find out if the balance of NAD+ and NADH was critical for tumor cell behavior, the team proceeded to insert a yeast gene into cancer cells that caused a shift toward more NAD+. To the scientists’ amazement, this shift caused the tumor cells to become less aggressive.

“It was a really happy moment for me,” said Santidrian. But the more exciting moments, he said, were yet to come.

To confirm and extend the initial findings, the team altered genes tied to NAD+ production. The resulting shift again showed that higher NADH levels meant more aggressive tumors, while increased NAD+ had the opposite effect.

The next logical step was to find a simple way to enhance the critical NAD+ level therapeutically. So the team explored what would happen if mice with breast cancer were fed water spiked with nicotinamide, a precursor for NAD+ production. The scientists found cancer development was dramatically slowed down, and the mice lived longer

“In animal models at various stages, we see that we can actually prevent progression of the disease,” said Felding."

 

_____________________________________________________________________________________________________

 

According to this, if I am reading it properly, NAD can be a preventer and also under certain circumstances helper of cancer. It seems it can help cancer along in later stages and be peventative by keeping cells healthy pr-cancer... Also, Glioblastomas mentioned in the link in Bryan's post are usually found at the later stage of the disease rather than at the early stages.

 

http://www.scitechno...article_id=5285


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#15 lumia

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Posted 07 December 2016 - 02:01 AM

 

Pathway linked to slower aging also fuels brain cancer

http://medicalxpress...ging-fuels.html

 

That's terrible. Hopefully none of us have existing tumors. I assume it's fine if you don't. I don't have a history of that kind of cancer in my family.

 

 

One of my grandfathers and his sibling died of brain cancer. Don't know which type. I don't know what this means anymore.


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#16 Harkijn

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Posted 07 December 2016 - 08:48 AM

 

 

Pathway linked to slower aging also fuels brain cancer

http://medicalxpress...ging-fuels.html

 

That's terrible. Hopefully none of us have existing tumors. I assume it's fine if you don't. I don't have a history of that kind of cancer in my family.

 

 

One of my grandfathers and his sibling died of brain cancer. Don't know which type. I don't know what this means anymore.

 

I think there is reason for some concern and that concern is wider than gioblastoma only. For their in vitro study, the researchers chose glioblastoma cells but we can assume that NAMPT works similarly in other cancers. This risk is not a totally novel finding, for the Aging Firewalls blog has extensively written about the dual nature of NAMPT. I am glad that results of human NR trials will be in rather soon.


Edited by harkijn, 07 December 2016 - 08:48 AM.


#17 Harkijn

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Posted 11 December 2016 - 08:35 AM

 

 

 

Pathway linked to slower aging also fuels brain cancer

http://medicalxpress...ging-fuels.html

 

We don't know what this study will reveal since it doesn't seem to be listed anywhere on pnas.org even though the 'press statement' states it was published Dec. 5 in Proceedings of the National Academy of Sciences. The primary author's lab publications list indicates it will be named 'NAMPT controls tumor growth and therapy responsiveness in glioblastoma'.

 

This study now shows up in the early edition listing... http://www.pnas.org/...921114.abstract

Unfortunately I don't have access to get behind his paywall. If anyone does and can post a link or summary...

 

file:///C:/Users/Eigenaar/Downloads/10.1073@pnas.1610921114.pdf

 

This is better:

 

http://www.pnas.org....921114.abstract


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#18 Baten

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Posted 11 December 2016 - 06:07 PM

file:///C:/Users/Eigenaar/Downloads/10.1073@pnas.1610921114.pdf

 

Your username is simply 'Owner'? :laugh: haha


Edited by Baten, 11 December 2016 - 06:07 PM.

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#19 Harkijn

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Posted 11 December 2016 - 08:23 PM

 

file:///C:/Users/Eigenaar/Downloads/10.1073@pnas.1610921114.pdf

 

Your username is simply 'Owner'? :laugh: haha

 

 

Like the old Masters of the East have said: the road to longevity is: keep life simple.  :)



#20 Daniel Cooper

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Posted 14 December 2016 - 03:47 PM

Nicotinamide riboside: From Discovery to Human Translation

I put in a request for you all and we'll see if they can stream the presentation.   ;)

 

Edit: I spoke with the Chair or the Department of Nutritional Sciences University of Wisconsin-Madison and he said they would put up a link for a few days after the event. No live stream but it appears we can see the event after the fact. I'll post more when I'm given the link.

 

 

Has Dr. Brenner ever addressed the concerns about cancer promotion?

 

It would be great if he were to speak about that study on NAD+ and glioblastoma.


Edited by Daniel Cooper, 14 December 2016 - 04:35 PM.


#21 Bryan_S

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Posted 24 April 2017 - 11:13 PM

Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign Lesions from Hepatic Progenitor Cells 

PDF (7 MB) - Cell http://www.cell.com/...(17)30420-5.pdf

 

 
SUMMARY

 

Hepatocellular carcinoma (HCC) is an aggressive primary liver cancer. However, its origin remains a debated question. Using human data and various hepatocarcinogenesis mouse models, we show that, in early stages, transformed hepatocytes, inde- pendent of their proliferation status, activate hepatic progenitor cell (HPC) expansion. Genetic lineage tracing of HPCs and hepatocytes reveals that, in all models, HCC originates from hepatocytes. However, whereas in various models tumors do not emanate from HPCs, tracking of progenitors in a model mimicking human hepatocarcinogenesis indi- cates that HPCs can generate benign lesions (regen- erative nodules and adenomas) and aggressive HCCs. Mechanistically, galectin-3 and a-ketogluta- rate paracrine signals emanating from oncogene-ex- pressing hepatocytes instruct HPCs toward HCCs. a-Ketoglutarate preserves an HPC undifferenti- ated state, and galectin-3 maintains HPC stemness, expansion, and aggressiveness. Pharmacological or genetic blockage of galectin-3 reduces HCC, and its expression in human HCC correlates with poor survival. Our findings may have clinical implications for liver regeneration and HCC therapy.
 
Switching off hURI expression with doxycycline significantly reduced HPC proliferation (Figures 6A and 6B), suggesting that continuous hURI expression is essential for oval cell expansion. Abrogation of DNA damage by supplying the NAD+ booster nicotinamide riboside (NR) (Tummala et al., 2014) reduced HPC proliferation in 8-week-old mice (Figures 6C–6E), suggest- ing that the NAD+-deficit-induced DNA damage axis is essential for oval cell expansion.

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#22 warner

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Posted 25 April 2017 - 02:15 AM

Since we're back talking about NR and cancer again, I guess I'll go ahead and post this review of that topic which I put together last December, but did not post, being put off by the tone of the discussion at that time.  The only change I've made since then is that I've gone back to 375 mg/d NR after finding a specific disease (glaucoma) that may benefit from higher dose.

 

NR Cancer Review - Part 1      12/2/2016

 

I’ve been away from this forum for a few weeks investigating in my spare time the possible link between NR supplementation and cancer, and whether this possible link should impact my NR dosing.  fwiw, what follows is a summary of what I’ve discovered, along with links to some of the key studies or reviews.  Additions, corrections, and comments welcome as always.

 

At this early stage, the direct effect of NR supplementation on cancer risk has not been well studied.  However, a substantial amount of work in recent years has been done investigating the inhibition of NAMPT, PARPs, and SIRT1 as a possible means of reducing cancer risk and progression.  This stems from the observation that, in most cases, NAMPT, PARPs, and SIRT1 are all up-regulated (increased expression and activity) in cancer cells, and that inhibition (reduced expression) of these reduces progression (improves prognosis).  The latter observation of reduced progression with inhibition is important, since it indicates that the increased activity of NAMPT, PARPs, and SIRT1 is not an attempt by the cell to reduce its cancerousness, but rather likely reflects coordinated support of the cell’s overall higher cancerous metabolic rate.

 

There are some exceptions to this rule, but they are very cancer-specific, and, tellingly, there has been little effort made to investigate the treatment of existing cancers by increasing PARP or SIRT1 expression, given the overwhelming evidence for the opposing effect.  Also note that the effect on cancer of other sirtuins is more complex, although the general rule that (in cancers of various types) increased sirtuin expression means better outcome with sirtuin inhibition, and decreased sirtuin expression means better outcome with sirtuin activation, is well-established across all of the sirtuins.  This table illustrates the rule, where “HIGH” refers to increased expression and likely susceptibility of the cancer to sirtuin inhibition, and “LOW” refers to decreased expression and likely susceptibility of the cancer to sirtuin activation (a “?” indicates some conflicting results for that cancer type):

 

SIRT1     HIGH:  breast(?), prostate, lung, colon, thyroid, gastic, liver, pancreatic, ovarian, cervical,

  CNS tumors, lymphoma, leukemia

              LOW:  head & neck squamous cell carcinoma (HNSCC)

 

SIRT2     HIGH:  cervical, bladder, pancreatic, neuroblastoma, leukemia, lung

                LOW:  gliomas, esophageal, gastric, HNSCC, breast(?), liver, BCC

 

SIRT3     HIGH:  oral squamous cell carcinoma, lymph-node-positive breast, gastric, esophogeal

                LOW:  breast, colon(?), HNSCC, liver, osteosarcoma, BCC, HNSCC, gastric

 

SIRT4     LOW:  bladder, breast, colon, gastric, ovarian, thyroid, lung

 

SIRT6     HIGH:  lyphocytic leukemia, breast

                LOW:  pancreatic, colorectal, liver, HNSCC

 

SIRT7     HIGH:  breast, thyroid, liver

                LOW:  HNSCC

 

The emerging and diverse roles of sirtuins in cancer:  a clinical perspective (2013)

https://www.ncbi.nlm...les/PMC3797239/

The Role of SIRT1 in Cancer:  The Saga Continues (2015)

https://www.ncbi.nlm...les/PMC4729271/

The Prognostic and Clinicopathological Roles of Sirtuin-3 in Various Cancers (2016)

https://www.ncbi.nlm...les/PMC4970700/

 

Note that for breast cancer, SIRT1 increases aromatase expression, and thus E2 levels, in breast tissue (a property claimed to be peculiar to primates).  Also, for breast cancer, we have a study showing that SIRT1 gene polymorphisms that increased lifelong SIRT1 level in humans were associated with increased breast cancer risk and progression.  Those breast cancer results call into question the proposition that SIRT1 activation may help prevent cancers while simultaneously promoting existing cancer.  The prevention side of things may be more complex and cancer-specific.

 

Clinicopathological and prognostic role of SIRT1 in breast cancer patients (2015)

https://www.ncbi.nlm...les/PMC4358491/

SIRT1 Positively Regulates Breast Cancer Associated Human Aromatase Expression (2013)

https://www.ncbi.nlm...les/PMC3589668/

Association between SIRT1 Gene Polymorphisms and Breast Cancer in Egyptians (2016)

http://journals.plos...al.pone.0151901


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#23 warner

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Posted 25 April 2017 - 02:18 AM

NR Cancer Review - Part 2

 

From the table above it looks like, for existing cancers, we can say with some confidence that SIRT1 promotes cancer progression, SIRT4 inhibits progression, and BCC and HNSCC may benefit from general sirtuin activation (as with NR supplementation).  Interestingly, BCC (basal cell carcinoma) is one of the oft-cited examples of B3 vitamin-based reduction of cancer risk, and the sirtuin inhibition research seems to support that (via NAD activation of sirtuins).

 

The expression levels of the sirtuins in patients with BCC (2016)

https://www.ncbi.nlm...pubmed/26631040

A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention (2015)

http://www.nejm.org/...6/NEJMoa1506197

 

Research into PARP inhibition yielded similar results to SIRT1:  PARP1 is generally up-regulated in most cancer types, and PARP1 inhibition reduces cancer progression.

 

PARP1   HIGH:  blood, breast, cervix, colon, endometrium, liver, lung, ovary, prostate, skin,

                  kidney, Ewing sarcoma, glioblastoma, meningiomas, laryngeal

 

Trial Watch – inhibiting PARP enzymes for anticancer therapy (2016)

https://www.ncbi.nlm...les/PMC4905370/

 

Again, one might speculate that PARP1 is being up-regulated in an attempt by the cell to save itself from its cancerous state, but PARP1 inhibition slows growth, showing that PARP1, along with SIRT1 and NAMPT, is likely an integral part of what supports the cancer cell’s increased metabolism and growth rate (i.e., PARP1 is helping to save the cancer cell, not reducing the cancerousness of the cell).

 

Finally, since NAMPT expression is greatly increased in nearly all cancers as part of their switch to a largely glycolysis-based metabolism, it makes sense that NAMPT inhibition would turn out to be a very effective way to suppress and kill cancer cells.  Unfortunately, NAMPT inhibition of greater than 90% is required to induce cancer cell death (typically occurring in 3-4 days), and the amount of inhibitor needed to reach that level of inhibition produces serious dose-limiting toxicities:  thrombocytopenia (loss of blood platelets), lymphopenia, GI effects, rash, and cardiac and retinal cell toxicity.  So far, in fact, in human trials, probably due to dose-limiting toxicity, the NAMPT inhibitors have been a complete bust as anti-cancer agents.

 

Inhibition of NAMPT as a therapeutic strategy in cancer (2015)

https://www.ncbi.nlm...pubmed/25709099

 

One proposed trick is to find cancers that lack NAPRT1 expression, which supports the niacin to NAD pathway, and to use niacin supplementation to support the body’s non-cancerous cell NAD needs while wiping out the NAPRT1-deficient cancer cells with an NAMPT inhibitor.  However, there are several problems with this approach:

                - most cancer cells retain NAPRT1 expression, meaning niacin would rescue them too

                - retinal toxicity was not rescued by niacin (leaving you cancer-free but blind?)

                - some researchers have shown the required 90+% NAMPT inhibition is easily undone

                    by systemic NAD sources (as in real in vivo experiments, vs. contrived in vitro)

So even the clever strategy of restricting use of NAMPT inhibitors to NAPRT1-deficient cancers, and using niacin to rescue the rest of the body, seems unlikely to work.

 

Loss of NAPRT1 Expression by Tumor-Specific Promoter Methylation Provides a Novel

  Predictive Biomarker for NAMPT Inhibitors (2013)

https://www.ncbi.nlm...pubmed/24097869

New strategies to maximize therapeutic opportunities for NAMPT inhibitors in oncology (2016)

https://www.ncbi.nlm...les/PMC4845202/

Supplementation of Nicotinic Acid with NAMPT Inhibitors Results in Loss of In Vivo Efficacy

  in NAPRT1-Deficient Tumor Models (2013)

https://www.ncbi.nlm...les/PMC3884523/

 

These failures have shifted tactics toward that of mixing SIRT1, PARP1, or NAMPT inhibitors with other sorts of anti-cancer chemotherapies, which may prove to be more successful.


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#24 warner

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Posted 25 April 2017 - 02:21 AM

NR Cancer Review - Part 3

 

So what about NR supplementation?  From the evidence presented above, I would guess that ageing skin, retina, and heart would benefit from NR, at least partially reversing the effects of reduced levels of NAD with age.  With respect to cancer progression, given the already large increase in NAMPT expression found in cancer cells, and their resistance to modest amounts of NAMPT inhibitors (>90% inhibition needed to kill), and ease of rescue from systemic sources of NAD, it seems unlikely that modest amounts of NR supplementation will make much difference to cancer progression (except, of course, in the case where the cells are being exposed to a lot of NAMPT inhibitor or related chemotherapy).  This also seems to be supported by the long history of NA and NAM supplementation not promoting cancer (at least not in any simple, dramatic way).

 

With respect to cancer risk (i.e., getting it started), as with progression, it’s hard to believe that maintaining NAD at youthful levels (although we’re not even sure how best to do that yet!) will add much (net) cancer risk, although the breast cancer results make me nervous, and might end up applying to other sex hormone-related cancers.  For that reason, we’ve (me & wife) decided to go back to 250 mg/d NR (125 mg on waking, 125 mg mid-afternoon) until better info is available, or at least until we encounter a specific disease that is known to respond well to greater NR supplementation.

 

Note that the current tradeoffs have a lot to do with the current intransigence of most cancers.  For example, if the only cancer one was worried about was BCC (basal cell carcinoma), and it was known that NR supplementation reduced risk, while increasing progression of existing BCC, then the optimum strategy might be to increase NR supplementation to reduce future risk while promoting faster growth of any existing BCC cells so that they could be more readily seen and removed (an effective and simple procedure).  So the better we get at dealing with cancer, the more the tradeoff would shift in the direction of maintaining a healthy metabolism, with cancer treatment being an occasional nuisance.

 

Finally, for a more upbeat perspective, you can take a look at these 2 papers that Bryan has referenced in past posts:

 

The Roles of SIRT1 in Cancer (2013)

https://www.ncbi.nlm...les/PMC3764469/

NAD+ in Cancer Prevention and Treatment:  Pros and Cons (2016)

http://www.scitechno...bstract_id=5285

 

But I found those papers to be misleading, being overly weighted with arguments in favor of SIRT1 and NAD+ augmentation, relative to the strong evidence that these factors are almost always involved in promoting existing cancer progression, and the lack of evidence to date that NR supplementation reduces net cancer risk.  imho


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#25 MikeDC

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Posted 25 April 2017 - 10:27 AM

Cancer cells delends on similar things for cell survival. So theoretically NR could help Cancer cells to
Survive as well as normal cells. So until clinical studies prove that NR cures cancer, Cancer patients should
Not use NR. We know they are studying Using NR on breast cancer right now.

In a mouse model, they have found that NR prevent and cure liver, pancreatic and breast cancer.
We can easily see the reason why NR can prevent cancer since NR increases DNA repair.
Why NR can cure cancer we don't know yet. Maybe it increases normal cells ability to fight cancer cells.
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#26 warner

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Posted 25 April 2017 - 01:03 PM

Summary of Key Points from Cancer Review:

 

1.  Cancers vary in whether they increase or decrease expression/activation of the various sirtuins, PARP, and NAMPT.

2.  There is strong evidence that this variation serves to enhance cancer progression (vs. an attempt by the cell to reduce cancer progression), meaning that cancers with high expression of particular sirtuins, PARP, or NAMPT are generally suppressed with inhibition of these factors, and vice versa.

3.  However, such attempts to slow cancer progression by inhibiting or activating these factors have generally not been successful (as cancer treatments) in isolation.

4.  With respect to NR supplementation and cancer progression, given the already large increase in NAMPT expression found in cancer cells, and their resistance to modest amounts of NAMPT inhibitors (>90% inhibition needed to kill), and ease of rescue from systemic sources of NAD, it seems unlikely that modest amounts of NR supplementation will make much difference to cancer progression.

5.  With respect to NR supplementation and cancer risk/initiation, the hypothesis that maintaining youthful levels of NAD+ will help prevent cancer is supported by isolated research such as that for non-melanoma skin cancer, but not by some of the breast cancer research.  However, it may be the case that the optimal solution (for longevity) is nonetheless to maintain NAD+ levels while finding new ways to fight the inevitable bouts of cancer accompanying aging.


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#27 HappyPaul

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Posted 30 June 2017 - 02:28 AM

Very interesting paper about using Vitamin C and Doxycycline: "A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)".  http://www.impactjou...28&path[]=59195

 

The relevant part that caught my eye and made me post it here in red bold:

Our current findings are in line with previous studies showing the highly plastic nature of CSCs allows them to adjust and adapt their metabolic environment, in order to maintain their distinctive properties, in a hostile tumor microenvironment, often characterized by an inadequate nutrient and oxygen supply (reviewed in [23]). Here, we have taken advantage of the glycolytic shift exhibited by DoxyR CSCs, as we have used several glycolysis inhibitors with the aim to turn their strict metabolic inflexibility, into a lethal phenotype. Among the agents tested in the our study, Vitamin C has been demonstrated to selectively kill cancer cells in vitro and to inhibit tumor growth in experimental mouse models [2425]. Remarkably, many of these actions have been attributed to the ability of Vitamin C to act as a glycolysis inhibitor, by targeting GAPDH and depleting the NAD pool

 

Does this seem to indicate that a depleted NAD pool is a requirement in order to allow vitamin C to kill the cancer cells and perhaps supplementation or NR to increase NAD could aid the CSCs from attack by cancer treatment?   Also wondering about if this means that NR supplementation to raise NAD would hurt other cancer treatments which focus on cutting off the cancers food supply through glycosis inhibition.  I have written to the authors but not heard back.  I understand NR can be used for treatment in post chemo neuropathy.  

 

A simplier explanation of the above paper is at http://jeffreydachmd...cancer-synergy/

--- "In an elegant study, Lisanti’s group created Doxycycline resistant cancer stem cells by successive passage of the cells through higher doses of Doxycycline treatments.   Most of the cells were killed by the doxycycline.  However the few surviving cells were then allowed to multiply and repopulate, and were again treated with higher doses of doxyxycline.  This process was repeated until final cells were indeed Doxycyline resistant, they were immune to the antibiotic. ---

 

The Dox-Resistant cancer cells were now sensitive to eradication with metabolic perturbation from high dose vitamin C.  Vitamin C acts as a glycolysis inhibitor, by targeting (GAPDH) Glyceraldehyde 3-phosphate dehydrogenase, 6th step in glycolysis.   Vitamin C also and depletes the (NAD) nicotinamide adenine dinucleotide pool.  High dose IV vitamin C easily reached serum concentrations for these lethal effects in the clinical setting.

 

Why vitamin C works is here https://www.scienced...70109134014.htm

"Cancer researchers have homed in on how high-dose vitamin C kills cancer cells. Vitamin C breaks down to generate hydrogen peroxide, which can damage tissue and DNA. The new study shows that tumor cells with low levels of catalase enzyme activity are much less capable of removing hydrogen peroxide than normal cells, and are more susceptible to damage and death when they are exposed to high doses of vitamin "

 

No flames please, just trying to figure this out as I deal with stage 4 cancer family member  currently undergoing chemo after numerous other treatments stopped working.  At some point within the next 12 months, chemo will stop working and am investigating Hail Mary options vs just giving up and going into palliative care at that time.  This IV Doxycycline regiment followed by IV vitamin C may not work but there seem to be no real side effects, it is inexpensive and I can't see a downside vs just giving up. I have been looking into how NR would affect them at that point.  The paper above gave me pause that the NR and NAD increase might be counter to some treatments trying to kill the cells. 

 

Thank you,

 

Paul


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#28 Razor444

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Posted 30 June 2017 - 11:06 AM

If it's similar to antioxidant capacity, then you'd want to increase capacity/NAD+ when you don't have cancer & deplete capacity/NAD+ when you do. The aim is: to fuck cancer cells up with oxidative stress.


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#29 MikeDC

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Posted 01 July 2017 - 02:18 PM

Very interesting paper about using Vitamin C and Doxycycline: "A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)". http://www.impactjou...28&path[]=59195

The relevant part that caught my eye and made me post it here in red bold:
Our current findings are in line with previous studies showing the highly plastic nature of CSCs allows them to adjust and adapt their metabolic environment, in order to maintain their distinctive properties, in a hostile tumor microenvironment, often characterized by an inadequate nutrient and oxygen supply (reviewed in [23]). Here, we have taken advantage of the glycolytic shift exhibited by DoxyR CSCs, as we have used several glycolysis inhibitors with the aim to turn their strict metabolic inflexibility, into a lethal phenotype. Among the agents tested in the our study, Vitamin C has been demonstrated to selectively kill cancer cells in vitro and to inhibit tumor growth in experimental mouse models [24, 25]. Remarkably, many of these actions have been attributed to the ability of Vitamin C to act as a glycolysis inhibitor, by targeting GAPDH and depleting the NAD pool

Does this seem to indicate that a depleted NAD pool is a requirement in order to allow vitamin C to kill the cancer cells and perhaps supplementation or NR to increase NAD could aid the CSCs from attack by cancer treatment? Also wondering about if this means that NR supplementation to raise NAD would hurt other cancer treatments which focus on cutting off the cancers food supply through glycosis inhibition. I have written to the authors but not heard back. I understand NR can be used for treatment in post chemo neuropathy.

A simplier explanation of the above paper is at http://jeffreydachmd...cancer-synergy/
--- "In an elegant study, Lisanti’s group created Doxycycline resistant cancer stem cells by successive passage of the cells through higher doses of Doxycycline treatments. Most of the cells were killed by the doxycycline. However the few surviving cells were then allowed to multiply and repopulate, and were again treated with higher doses of doxyxycline. This process was repeated until final cells were indeed Doxycyline resistant, they were immune to the antibiotic. ---

The Dox-Resistant cancer cells were now sensitive to eradication with metabolic perturbation from high dose vitamin C. Vitamin C acts as a glycolysis inhibitor, by targeting (GAPDH) Glyceraldehyde 3-phosphate dehydrogenase, 6th step in glycolysis. Vitamin C also and depletes the (NAD) nicotinamide adenine dinucleotide pool. High dose IV vitamin C easily reached serum concentrations for these lethal effects in the clinical setting.

Why vitamin C works is here https://www.scienced...70109134014.htm
"Cancer researchers have homed in on how high-dose vitamin C kills cancer cells. Vitamin C breaks down to generate hydrogen peroxide, which can damage tissue and DNA. The new study shows that tumor cells with low levels of catalase enzyme activity are much less capable of removing hydrogen peroxide than normal cells, and are more susceptible to damage and death when they are exposed to high doses of vitamin "

No flames please, just trying to figure this out as I deal with stage 4 cancer family member currently undergoing chemo after numerous other treatments stopped working. At some point within the next 12 months, chemo will stop working and am investigating Hail Mary options vs just giving up and going into palliative care at that time. This IV Doxycycline regiment followed by IV vitamin C may not work but there seem to be no real side effects, it is inexpensive and I can't see a downside vs just giving up. I have been looking into how NR would affect them at that point. The paper above gave me pause that the NR and NAD increase might be counter to some treatments trying to kill the cells.

Thank you,

Paul


If you can kill all cancer cells with chemo, then NR is not good since it will help cancer cells to survive. But if you don't kill all the cancer cells, NR actually prevent the growth and migration. So the best strategy is to kill as much cancer cells as you can and then starting taking NR to prevent recurrence of cancer.

#30 HappyPaul

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Posted 02 July 2017 - 12:31 AM

 

If you can kill all cancer cells with chemo, then NR is not good since it will help cancer cells to survive. But if you don't kill all the cancer cells, NR actually prevent the growth and migration. So the best strategy is to kill as much cancer cells as you can and then starting taking NR to prevent recurrence of cancer.

 

This does not maker seems to me.  It seems like you would take NR before you had cancer to try and keep errors away which cause cancer but the moment you have a cancer concern, stop NR and don't go near it as it can feed cancer cells and it looks like it would work against many cancer treatments which seek to starve cancer cells which reproduce so much faster.  Thoughts? 


Edited by HappyPaul, 02 July 2017 - 12:32 AM.






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