The role of NAD in cancer
If the body does not get enough NAD (nicotinamide adenine dinucleotide); this can mean low tryptophan levels signal the body to lower the immune system and accept certain bacteria such as tuberculosis (TB) [1].
Therefore, is the immune system lowered in relation to cancer cells, because the body is not getting sufficient NAD and because tryptophan is low?
Self-renewing cancer stem cells have excess NADH. This was from a study on cancer cells resistant to the drug Gleevec, in leukemia [2].
In light of the link between NAD, the immune system and cancer cells I am posing a few questions - for the 'NAD experts' - or anyone who can comment or correct my line of questioning. Please leave your comments.
Question 1) Do cancer cells lower the immune system in order to store extra NADH?
Question 2) Is it possible the immune system is only lowered against cancer stem cells when there is insufficient NAD in the body?
Question 3) Might we restore immune attack against cancer stem cells if we engineer cancer stem cells so that they do not harbour excess NADH ? Or ensure the body has sufficient NADH so that storage is no longer neccessary?
Question 4) Since NADH can be easily measured due to the UV light absorbed by adenine, can we use NAD as a biomarker for cancer stem cells?
Question 5) If tryptophan or niacin pathways to NADH are faulty - despite obtaining sufficient tryptophan from the diet - then can we fix these pathways in order to restore the immune system?
Question 6) Are bacteria/viruses responsible for the 'faulty pathway' for instance low tryptophan? If we identify which bacteria and viruses can we target them to prevent cancer stem cells with excess NADH?
Given some of the links to NADH and cancer stem cells, I thought it might be useful to list some properties of NAD here. If you like your science simple - then this section is not for you.
Properties of NADH (Nicotinamide Adenine dinucleotide + hydrogen):
Nicotinamide is found in vitamin B3 (niacin) and adenine is one of the DNA bases.
NAD comes from tryptophan or from Vitamin B3 (Niacin).
Tryptophan can be sourced from meat [1].
NAD is essential for metabolism and development, regulating reproduction, DNA repair, ageing, donation of electrons and more.
NAD and NADH strongly absorbs UV light because of the adenine (which has a conjugated structure lending itself to UV light absorption.) That is how it is measured and both NAD and NADH have differering flourescence lifetimes [3].
Nicotinamide enhances repair of DNA damage induced by UV radiation [4].
Nicotinamide is an anti-inflammatory.
Nicotinamide used to treat acne does not result in resistance, but the acne might return when usage is stopped.
NAD from tryptophan and niacin pathways do not offer the organisms infleunza, candida or chlamydia access to NAD - they must get the NAD from their host.
NAD production can be stimulated by Toxoplasma gondii, Leishmania, and Chlamydia , but at the same time the infections might consume tryptophan to grow.
And at the same time the organisms might produce toxic compounds.
The IDO enzyme can stop these bacteria, but unfortunately the IDO enzyme also stops T cells, so cancer cells might then escape immune surveillance.
NAD deficiencies can be experienced if we have intestinal overgrowth.
NADH deficiencies can result in the generation of too much reactive oxygen species (ROS) that the body cannot deal with [5].
If there is insufficient NAD then excess ROS and hence excess antioxidants such as glutathione; may be generated to deal with excess ROS [5].
Recall we do need ROS since it ensures apoptosis (programmed death) of cells that should die [5].
Given we need enough ROS, we also need the P53 gene to work in low Myc conditions, to turn on genes that make ROS [5] [6].
More NADH and low oxygen consumption is found in mitochondria (subunits within cells) of self-renewing cancer stem cells according to research by Kluza, Jendoubi et al [2].
The body might lower the immune system when it does not obtain enough NADH, in order to accept bacteria like TB, which can supply it with this NADH [1].
In times in history when we haven't had enough meat, the body appears to have lowered the immune system to accept bacteria such as tubercolosis (TB) [1].
Low tryptophan is associated with a lower immune system.
Drugs impacted
Sanofi's Eflornithine and Sulindac by Cancer Prevention Pharma is a preventative program in a Phase 3 trial already used for African sleeping sickness or trypanosomiasis (a name for several parasitic diseases from tsetse fly bites) Of interest is that bacteria such as leishmania can upregulate NAD, but consume tryptophan.
Boston Biomedical works with stem cell agents and chemotherapy to establish whether cancer stem cells can differentiate into normal cells that can then be treated with chemotherapy. I haven't noted specific mention of NAD, but this may be impacted. Refer colorectal cancer drugs and stem cells.
References (NAD)
[1] 'Big Brains, Meat, Tuberculosis, and the Nicotinamide Switches: Co-Evolutionary Relationships with Modern Repercussions?' Adrian C. Williams and Robin I.M. Dunbar et al. 15 Oct 2013.
[2] 'Exploiting Mitochondrial Dysfunction for Effective Elimination of Imatinib-Resistant Leukemic Cells', Jérome Kluza, Manel Jendoubi et al. July 18 2011.
[3] [6] Fluorescence lifetime imaging of free and protein-bound NADH.J R Lakowicz, H Szmacinski et al. Feb 1992.
[4] Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in human keratinocytes and ex vivo skin, Surjana D, Halliday GM et al. May 2013 Pubmed.
[5] Oxidants, antioxidants and the current incurability of metastatic cancers, Jim Watson, published 9 January 2013. DOI: 10.1098/rsob.120144; The Lancet March 1-7, 2014. Extracts from Cold Spring Harbour Laboratory 27 Feb 2014.
[6] Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. 2009 Metformin selectively targets cancer stem cells and acts together with chemotherapy to block tumour growth and prolong remission. Cancer Res. 69, 7507–7511. Doi: 10.1158/0008-5472.CAN-09-2994 (doi: 10.1158/0008-5472.CAN-09-2994)).
