Nicotinamide/NAD+ and CLL

[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

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