Diäten, Gewichtsreduktion, Heilfasten » Lapacho-Tee

ß-Lapachon steigert NQO1-Enzymaktivität sehr effektiv. Das wiederum steigert die intrazelluläre NAD/NADH-Ratio. Aber auch in Krebszellen.
http://www.anti-agingfirewalls.com/2015/...-interventions/

1, NQO1 regulates the intracellular redox state of the cell and thus, the ratio of NAD/NADH in the cell.

This is the main reason why I now think that NQO1 is so important. Mice that are homozygous negative (both genes knocked out) for NQO1 have an increase in the NADH/NAD ratio (and an increase in the NADPH/NADP ratio). NQO1 knockout mice strangely enough have lower blood glucose levels, less abdominal fat. However, they have higher levels of triglycerides, beta-hydroxybutyrate, pyruvate, and lactate. They also have higher levels of glucagon. More importantly, the NQO1 “knock out” mice have lowered rates of pyridine nucleotide synthesis, reduced glucose metabolism, and reduced fatty acid metabolism. This is not surprising since NQO1 is the controller of the 20S PC mediated degradation of PGC-1alpha.

Unfortunately, cancer cells have also discovered this wonderful property of NQO1. Many cancers unregulate NQO1 either via Nrf2 pathways or by other methods, such as the loss of miR suppression of mRNA for NQO1. A recent study shows that higher levels of the NQO1 protein predict poor prognosis in non-small cell lung cancer. This is a sobering thought – cancer cells up-regulate antioxidant genes! This does not mean that we should avoid phytosubstances that up-regulate NQO1, it just means that “cancer cells are smart”.

Introducing: BET proteins

The opposite problem occurs in aging cells. Aging cells have lower levels of expression of the gene NQO1. This is not just due to a “lack of broccoli” or a “lack of exercise”. Instead, the gene NQO1 is down-regulated by proteins called “epigenetic readers”. The two “epigenetic readers” that suppress the Nrf2-induction of the NQO1 gene are called “Bromodomain and Extraterminal Proteins” (or BET proteins). Specifically, Brd2 and Brd4 proteins “sit on top” of the histone protein acetylated lysines at the promoters of the Nrf2-dependent genes. As a consequence, Nrf2 and the other transcription factors that “turn on” NQO1 gene cannot turn the gene on. (This is why BET inhibitors like JQ1 are so exciting).

Summary: NQO1 regulates the ratio of NAD/NADH and the ratio of NADP/NADPH by oxidizing NADH to NAD+. Warburg-type metabolism ensures that most of the NAD(H) within the cell is in the reduced form (NADH). NQO1 is one of the few genes that oxidizes NADH to NAD+. When both genes for NQO1 are “knocked out”, there is even more NADH in the reduced state. This results in a lower NAD/NADH ratio (or higher NADH/NAD ratio). Thus, NQO1 is the “anti-Warburg gene”. This is why NQO1 is so important.



Im gleichen Blog werden dann aber die Anti-Krebs-Eigenschaften von ß-Lapachon aufgeführt:

0. Beta-lapachone, a compound found in the bark of the South American Lapacho tree, is a potent activator of the NQO1 protein and produces ROS in cancer cells, but reduces ROS in non-cancer cells. It also inhibits pathological retinal neovascularization, but does not inhibit physiological neovascularization.

The most exciting thing about NQO1 is that there is a natural, cheap, compound found in the tree bark of a South American tree. The compound is called beta-Lapachone and is a NQO1 activator. Specifically, NQO1 is a “two-electron transfer” enzyme that can extinguish free radicals in normal cells, but produces free radicals in cancer cells. It has been shown to be a very effective compound for treating lung cancer. Here is how it works:

Beta-lapachone undergoes a redox cycle by NQO1, which reduces beta-lapachone to an unstable semiquinone. The semiquinone then rapidly undergoes a two-step oxidation back to the parent stable compound, beta-lapachone. This produces what is called a “perpetuating futile redox cycle”. This results in an unbalance of intracellular reactive oxygen species in cancer cells, resulting in the cell death of the cancer cells. This “perpetual futile redox cycle” is totally dependent on the concentration of NQO1 within cells. Here is a diagram of the reaction:

PT4-a

Illustration reference: 2014 The Chemotherapeutic Effects of Lapacho Tree Extract: β-Lapachone

The downstream effects of perpetual futile redox cycling include 4 apoptotic pathways and one necroptotic pathway:

Mitochondrial-induced apoptosis – The induction of ROS in mitochondria opens the MPTP pores and results in PARP activation and caspace activation. This induces apoptosis.
ER-induced apoptosis – The induction of ER stress induces sarcoplasmic release of calcium which induces high levels of cytoplasmic Ca++. This also induces apoptosis via the ER.
DNA-damage mediated apoptosis – beta-lapachone also induces Topoisomerase I and II. The activation of topoisomerases induces DNA breaks, which induces PARPs. This PARP hyper-activation induces apoptosis independently from mitochondrial ROS or ER stress.
Cell cycle arrest-induced apoptosis – The futile redox cycling of beta-lapachone also induces cycle cycle arrest via the activation of p21, p27, and the phosphorylation of JNK, PI3K, and Akt. This induces cancer cell apoptosis as well.
Calpain-induced cell necrosis – Unlike the 4 pathways above, futile redox cycling also induces calcium influx into the cells independently of ER stress. This calcium influx into the cell activates Calpain, which induces cell death by the necrosis pathway, not the apoptosis pathway.

Conclusion: beta-lapachone induces cancer cell death by five different pathways, all dependent on perpetual futile redox cycling which is dependent on NQO1