Re: Nicotinamide/NAD+ and CLL

[Guest guest]

So if niacinamide is a precusor of NAD+, which you write " is a critical cofactor

for many

enzymes, especially enzymes of energy-related metabolic pathways, which are

highly regulated in

cancer cells, so as to better fuel cancer cell proliferation " , then would

supplementation of this ordinary B vitamin actually fuel

the growth of the cancer?

I'm sorry, I don't think niacinamide will do anything one way or another in

fighting cancer. How many years as this vitamin been available?

Being a water-soluble vitamin, it is frequently used in megadoses for one reason

or another. I'm sure someone in the millions who have taken this vitamin has

had cancer. The fact that we have heard nothing about any cancer cure from

niacinamide suggests that, in vivo, it has little to no effect.

I don't want to encourage people to take huge doses of this vitamin, thinking it

will treat their CLL.

As Muir said, if you pick something up, you find it hitched to everything

else in the universe. Nothing in the body exists in isolation; nature uses the

same chemicals to do any number of functions. That's why every substance has

side effects, sadly.

________________________________

From: Al Janski <aljanski@...>

Cc: W.W.WELLS@...; TERJOHA@...; .Byrd@...;

nbartlet@...; chaya@...

Sent: Tue, July 5, 2011 12:48:51 PM

Subject: Nicotinamide/NAD+ and CLL

Re: " Nicotinamide Blocks

Proliferation and Induces Apoptosis of CLL Cells

through Activation of the p53/miR-34a/SIRT1 Tumor

Suppressor Network " ; Cancer Res; 71(13);

4473­83.; Deaglio & coworkers. Abstract: http://tinyurl.com/5s7ptvk

Re: Nicotinamide and CLL

At 06:25 PM 7/4/2011, S wrote:

>Nicotinamide ........ a commonly used vitamin in megadose therapy .........

As the abstract of the paper details,

nicotinamide is now known to be more than just a

vitamin supplement for nutrition. Nicotinamide

is more important for regulating cellular

activities than we would have guessed 30 yrs ago,

when I was doing metabolism research at the NIH.

At 06:25 PM 7/4/2011, S wrote:

>I doubt that we have overlooked the affect on CLL from this vitamin.

What metabolic pathways are doing within a cancer

cell defines what that cancer cell will or will

not do. Very little is known about the metabolic

pathways, and their regulation, in CLL cells,

even in vitro, let alone within the clinically

relevant, but complex, in vivo microenvironments,

in which those CLL cells do their damage.

Nicotinamide's important roles as a

substrate/product within, and a regulator of, a

wide variety of pathways in normal cell function,

by definition, make it one of the more important

metabolites/regulators for which there is a need

for greater understanding of CLL cell metabolism

in the process of defining better care of CLL.

At 06:25 PM 7/4/2011, S wrote:

>I don't think niacinamide as a single agent will

>do anything to treat CLL. Perhaps, in

>combination, it may prove to have an effect.

Use of nicotinamide in combination therapy is

what the authors meant in the abstract by " ....

to be used in addition to chemotherapy for CLL

patients with wt p53 " [ " wt p53 " is an

abbreviation for wild-type CLL cells, that have a functional p53 protein].

The authors further elaborate in the " Discussion "

in the paper, concluding: " The above results may

provide a preliminary rationale for the design of

a clinical trial to test the effects of oral

administration of nicotinamide in combination

with DNA damaging chemotherapeutics in CLL patients with wt p53. "

Although I think it is important the authors

(Deaglio & coworkers) are researching

nicotinamide, I do not expect either the research

nor the therapeutic applications to be simple.

For example, as the abstract indicates,

nicotinamide is the primary precursor metabolite

of another, even more important, metabolite,

NAD+, which is a critical cofactor for many

enzymes, especially enzymes of energy-related

metabolic pathways, which are highly regulated in

cancer cells, so as to better fuel cancer cell

proliferation. NAD+, in turn, is a source of

other critical regulatory metabolites, including

AMP, which is the primary regulator (activator)

of the enzyme AMP kinase (AMPK), and AMPK is

thought of as the " metabolic fuel gauge "

(allowing apoptosis), through which the diabetes

drug Metformin has its effects, and which has

been reported to induce apoptosis in CLL cells.

In this Cancer Research paper, Deaglio &

coworkers report, in their in vitro experiments,

that nicotinamide inhibits SIRT1, thus inhibiting

deacetylation of p53, thus allowing CLL

apoptosis. Others have observed that AMPK

enhances SIRT1 activity by increasing 'cellular'

NAD+ levels (Canto et al. Vol 458, 23 April 2009,

Nature, letter, doi:10.1038/nature0781).

Deaglio & coworkers have another recently

published paper [ " NAD+ - metabolizing

ecto-enzymes shape tumor–host interactions: The

chronic lymphocytic leukemia model " , T. Vaisitti

et al. ], a review of how the in vivo CLL

microenvironment is both nurished and regulated

by 'extracellular' NAD+, which serves as a

chemokine when it is extracellular. The review

discussion includes how CD38 (on CLL cell

membranes) is an enzyme (an " NADase " ) that

participates by breaking down NAD+ into adenosine

dinucleotide phosphate ribose (ADPR) and nicotinamide.

FEBS Letters 585 (June2011) 1514–1520; Free

full-text at http://tinyurl.com/3n948fj

Neither the Cancer Research paper nor the FEBS

Letters paper discussed what the expected effect

would be of oral administration of nicotinamide

on the highly regulated NAD+ metabolism in the

extracellular space of these CLL cells'

microenvironments. That may be a coincidence of

both papers being published close in

time. However, because there is so much going on

metabolically related to nicotinamide and NAD+,

I'm looking forward to their future papers where

they may make that speculation or even have direct data.

Nevertheless, this type of research is important

in building an understanding the complexities of

CLL metabolism, which will enable better strategies for therapy.

Al Janski

[Guest guest]

Re: " Nicotinamide Blocks

Proliferation and Induces Apoptosis of CLL Cells

through Activation of the p53/miR-34a/SIRT1 Tumor

Suppressor Network " ; Cancer Res; 71(13);

4473­83.; Deaglio & coworkers. Abstract: http://tinyurl.com/5s7ptvk

At 11:13 AM 7/6/2011, S wrote:

>I don't think niacinamide will do anything one

>way or another in fighting cancer.

[niacinamide = nicotinamide]

Deaglio & coworkers suggestion that nicotinamide

has therapeutic potential in combination with

other drugs is being clinically evaluated for

lymphomas in a Phase1 study, in combination with

etoposide (for NHL) and vorinostat (

http://clinicaltrials.gov/ct2/show/NCT00691210

). Etoposide (a DNA-damaging agent that

activates the p53 pathway) is the agent used in

combination with nicotinamide in the in vitro CLL

cell studies in this Deaglio paper. The safety

of high-dose nicotinamide will be assessed in this clinical study.

Deaglio did not seem to indicate nicotinamide was

ready for clinical evaluation in CLL

patients. The last sentence of the paper, after

referencing the above ongoing clinical study,

is: " Future studies will confirm whether

nicotinamide has potential as a novel, safe, and

inexpensive drug to be used in combination with

chemotherapy also for CLL patients with a wt p53 protein. "

At 11:13 AM 7/6/2011, S wrote:

>So if niacinamide is a precusor of NAD+, which

>you write " is a critical cofactor for many

>enzymes, especially enzymes of energy-related

>metabolic pathways, which are highly regulated

>in cancer cells, so as to better fuel cancer

>cell proliferation " , then would supplementation

>of this ordinary B vitamin actually fuel the growth of the cancer?

The phrase " energy-related metabolic pathways "

includes both pathways that 'increase' energy for

cancer cell proliferation as well as pathways

that 'decrease' energy for cancer cell

proliferation. NAD+ is a cofactor for enzymes in both types of pathways.

Further, it can not be assumed that by increasing

the precursor of a metabolite that will increase

the effects of that metabolite. Part of the

reason for that is that metabolic enzyme

reactions that convert one molecule to another

molecule can go in both directions, and more than

one enzyme can catalyze a unique reaction in each

direction, with different companion starting

substrates and different ending companion

products, and each enzyme can be under the control of different regulators.

One of the most common metabolic switches for

regulation is product inhibition. For example,

SIRT1 is a focus of this Deaglio paper. SIRT1

deacetylates lysine residues on proteins,

changing the functions of those proteins. When

p53 protein is deacetylated, it is less

active. That SIRT1 reaction involves the

consumption of NAD+ and the release of free

nicotinamide, which is a feedback product

inhibitor of SIRT1. That feedback inhibition is

the primary mechanism by which Deaglio theorizes

that nicotinamide can increase p53 activity (in

CLL cells that do not have inactivating p53

mutations or p53 gene deletions) and add to the

benefits derived from DNA-damaging

chemotherapeutics. In fact, that's what Deaglio

demonstrated with their CLL cell in vitro

experiments, using etoposide (an inhibitor of

topoisomerase II) as the combo chemotherapeutic.

However, because nicotinamide has many other

effects on other cells, including stromal cells

within the microenvironments in which CLL cells

do their damage, it is not at all certain that

efficacy (proliferation inhibition & apoptosis

activation) observed in vitro culture of CLL

cells will be realized with in vivo use of nicotinamide.

Certainly, as discussed in my previous post, the

fact that NAD+ metabolism is highly regulated in

the 'extracellular' space of the

microenvironments (as reported in a separate

recent paper by Deaglio and coworkers), could

have a major influence on whether what was

observed for isolated CLL cells predicts what is

observed for the in vivo use of

nicotinamide. This knowledge may be part of why

Deaglio inferred that nicotinamide was not yet

ready for clinical evaluation, and I would not be

surprised to see another paper by Deaglo's group that addresses this issue.

Additionally, even the intracellular metabolism

that is being referenced by Deaglio is built upon

knowledge of intracellular metabolism that was

determined for other types of cells, not CLL

cells. To be certain all these related metabolic

behaviors exist in CLL cells, they need to be

measured in CLL cells, and, preferably, in the

clinically important microenvironments in which

CLL cells exist, minimally using simulations of

those microenviroments (e.g. using stromal cell co-cultures, animal models).

The bottom line is that there is not yet enough

known about the metabolic pathways of CLL cells,

and their surrounding stromal cells, within their

pathogenic microenvironments, to accurately

predict effects of exogenously administered

metabolites (e.g. nicotinamide) that are critical

components in both the CLL cells and the stromal

cells and other cells that can directly or

indirectly affect outcomes. Such complexity is

just part of the territory when using metabolites

that are common to all cells to try to influence a specific outcome.

Nevertheless, despite these deficiencies, this

type of research in the nicotinamide paper is

important in helping build a better foundational

understanding of the complexities of CLL

metabolism, so as to enable better strategies for

therapy, with any type of therapeutic agent.

Al Janski

Reference:

" NAD+ - metabolizing ecto-enzymes shape

tumor–host interactions: The chronic lymphocytic

leukemia model " , T. Vaisitti et al. (Deaglio & coworkers)

FEBS Letters 585 (June2011) 1514–1520; Free

full-text at http://tinyurl.com/3n948fj

[Guest guest]

Hi Al, It's often said that mechanism of action (theory of same) is not

evidence, and your piece nicely explains why in a particular case.

Many thanks,

Karl