Any model we use to understand a biological system is simplistic, and not correct. As such, I wanted to start this section with actual results.
I looked at a few studies that said “all phytochemicals that contain electrophiles that with weak affinity for electrons have a significant toxicity towards numerous cancer cell lines”. It appears to me (and the study authors I think) that the toxicity is not due to actual photochemical induced damage to the cancer cells, but to up-gegulation of tumour suppression genes that occurs as a result. Additionally, as we age we start to generate errors in the expression of genes. It appears that phytochemicals also correct errors in gene expression.
It should be noted that gingerols, sulphoraphane and allicin are all chemically related and work largely the same way. The studies below show significant toxicity of gingerols and related compounds.
Prostate cancer
Here, we show that whole ginger extract (GE) exerts significant growth-inhibitory and death-inductory effects in a spectrum of prostate cancer cells.
Look at figure #1. No cancer cell line can survive ginger concentrations of 1,000 ug/ml. The black and pink lines are controls. This is kind of a beautiful picture for me, because leukaemia cells are similar. It means that my ginger experiment killed any remaining cancer cells in a quick death by suicide.
Figure #4 illustrations a significant reduction in tumour progression.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3426621/#!po=28.4884
The study below looks at the effects of circumin. Figure 1A shows that circumin concentrations of 100uM will kill any cancer cell.
This part is important…
To establish that curcumin-induced cell death was through apoptosis, we have studied oligo nucleosomal DNA fragmentation in all the cell lines. Curcumin treatment induced cellular DNA fragmentation in all the three tumor cells lines; however, no DNA fragmentation was observed in normal hepatocytes (Fig. 2A).
The fact that they died from apoptosis and not DNA damage (DNA fragmentation) means that the cells committed suicide. It appears that the ginger caused an up-gregulation of tumor suppression genes.
http://mct.aacrjournals.org/content/3/9/1101#T1
The question becomes…
Why Do Gingerol, sulphoraphane, allicin, etc selectively kills tumor cells?
It looks like the primary answer lies in increased gene expression from histone acetylation. Cancer is usually a result of improper gene expression. This can be in the form of hyper-methylation of a oncogene or hypo-methylation of a tumour suppression gene. An oncogene is a gene that leads to cancer when over expressed (state of hyper-methylation).
We also have tumor suppression genes. These do what you’d expect, and cause cancer cells to undergo apoptosis. Tumor suppression genes generally need these to be turned off for cancer to progress , and they usually are in cancer cell lines. Improper gene expression creates a situation where DNA mutations can occur without being corrected and lead to cancer.
I’d like to go back to my resting heart rate. It jumped from 42 to 68 after my experiment with ginger. It’s been gradually falling, but it’s still significantly elevated. Increased gene expression would be consistent with an increased resting heart rate as well as increased recovery rate.
There are a few ways to achieve a genome level increase in gene expression. Histone acetylation (https://en.m.wikipedia.org/wiki/Histone_acetylation_and_deacetylation) is the most likely candidate. Acetylation has been closely associated with increases in transcriptional activation while deacetylation has been linked with transcriptional deactivation.
During acetylation, the DNA becomes less tightly bound around the chromatin. This makes it easier for the enzyme RNA polymerase to come into contact with the DNA and initiate gene expression. Gene expression is where a particular segment of DNA is copied into RNA (especially mRNA) by the enzyme RNA polymerase. A protein is created, and the protein is involved in initiating a signalling network (getting your body to do something useful and necessary).
This type of response to perceived DNA damage makes sense. The best way to recover from damage (your body thinks it’s under attack when you eat ginger) is to upregulate gene expression and do more good stuff. In theory, the good stuff will help your body recover.
This explanation also explains why the results of my ginger experiment would persist for so long. While histone acetylation is plastic, the effects persist for some time. It wouldn’t be unreasonable to postulate that they might persist for months, or even a few years. So, the question becomes “Do we have evidence of regulation of histone acetylation via phytochemicals?
Studies Showing Up-regulation of histone acetylation.
This study shows how sulforaphane increased histone acetylation, globally, as well as locally in association with P21 and baxpromoters; 3) increased p21 and Bax mRNA and protein expression. Essentially, this paper goes thru the mechanic of how it works.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373266/#!po=36.6667
Below is a website that essentially says the same thing.
“The up-regulation of gene expression caused by sulforaphane appears they work by depressing the TOPflash promoter resulting in up to a doubling of acetylation as measured by histone H3 and H4.”
https://examine.com/supplements/sulforaphane/
It seems well established that these phytochemicals up-regulate gene expression through histone acetylation.
NRF2
It appears that there are some more transitory effects for the ginger as well. These transits effects are probably largely related to up-regulation of the NRF2 are related signalling networks. There is also evidence for increased amounts of glutathione. While these effects are advantageous to fighting cancer, the effects are transitory.
I suspect there is some crosstalk between NRF2 and histone acetylation. My hunch is that NRF2 initiates the increase in histone acetylation.
The stability of NRF2 is controlled by keap1. Keap1 is very sensitive to ROS. When ROS encounters KEAP1, it causes it to be inactivated. When this happens, the stability of NRF2 increases, and the concentration increases. More info is here:
http://www.mdpi.com/2072-6643/6/9/3777/pdf
So, we know that ginger would increase NRF2. The only question is if the NRF2 is responsible for the regulation of histone acetylation.
There are a few common items such as p300 that seem to regulate both NRF2 and histone regulation:
https://www.ncbi.nlm.nih.gov/pubmed/19273602
http://www.evexdb.org/ensembl/events/38576677/.
We know that histone acytelation is regulated by ROS levels. We just don’t know exactly how:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941536/#!po=43.1034
At this time, while I feel that NRF2 important, I don’t think it’s necessary to fully elucidate it’s role.