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Getting a Good "Flush"


Apoptosis - Extrinsic vs Intrinsic
I discovered some methods the past few months while reading cancer research, that are I believe (disclaimer) are helping/working in the fight against Jaymun's AML. Since, as a parent, I can only use natural supplements, I focused on apoptosis signaling therapy as the biggest "bang for the herbal buck".
See July 2005 Blood: Apoptosis-based therapies for hematologic malignancies
...this great website: www.researchapoptosis.com
...and Feb 2007 Carcinogenesis: Apoptosis by dietary factors: the suicide solution for delaying cancer growth.

Apoptosis serves an important cellular purpose. Each cell has a programmed way to shut itself down when damaged, or to be shut down by the immune system when "instructed" to do so. That mechanism of cell death is called apoptosis. When apoptosis works properly then useless or dangerous cells are eliminated - the immune system can effectively instruct cancer cells to "go away". When apoptosis is inhibited then those dysfunctional cells outpace the growth/survival of normal cells and collect as cancerous tumors. As the immune system picks off the cancer cells most able to execute apoptosis, natural selection increases tumor malignancy. Cells with apoptotic problems resist both natural elimination and medical treatment.

Interestingly on the flip side, oncogenes that control cell growth also can directly affect apoptosis. Mutations in oncogenes that stimulate "abnormal growth" also should accelerate cell death. So in order for cancer to be malignant, the oncogenic and apoptotic defects must be paired. That way the cells listen to the "loud" oncogenic growth signals while supressing the the "loud" apoptosis pressure. (2001 May Nature: Proliferation, cell cycle and apoptosis in cancer.) The point? Compensate for apoptosis defects, and the mutated environment will "assist" in destroying cancer.

Learn the Pathways: The apoptosis machinery is complex - like an electrical schematic or engineering diagram. There are several pathways which eventually converge, providing alternative "failsafe" ways for cells to shut down despite difficulties. I'll give you a simple analogy:

You push the lever
...which moves the bar
...which pulls the chain
...which raises the flap
...which empties the tank
...which flushes the bowl.

I just described the toilet-flush "pathway" for getting rid of unwanted "material" :)
The extrinsic pathway(s) of apoptosis work somewhat the same. And there are also intrinsic pathway(s) (activated by chemo, radiation, etc.) which are like dumping a bucket of water in the bowl of the toilet and forcing a quick, shortcut flush. In all pathways a successful flush has the same result - the convergance pathway (the caspases) down the drain.

Unreliable, Clogged, or Disabled Pathways: There are problems that can occur in either the "upstream" pathways or the joint "downstream" pathway. Apoptosis failure is a big part of how cancer gets out of control and becomes a malignant tumor. Let's say the float is stuck, the chain is too long, or the lever too short or hard to push - then you wouldn't get a flush at all (extrinsic problem - example). Let's say there is too much toilet tissue in the bowl and the entrance to the bottom of the toilet is plugged (intrinsic problem - example). Since both pathways eventually meet at the drain under the toilet you could have a plug there (convergence problem - example) that would make any sort of attempt to flush ineffective.

When I started studying leukemia in May, my first impression of how cancer is resistant to treatment was that the cells were stronger, hiding out, or not dividing at the time of treatment. That these cells would multiply into an entire population of genetically or locationaly resistant cells. However, upon further study I discovered things that piqued my interest.

There are actually moving parts (proteins, genes, etc.) in the cells, sequential genetic / chemical reactions that progress to either transmit and execute death signals, and/or maintain cellular survival. These "moving parts" can get stuck, or experience temporary levels of expression (low or high) that "stop the flush", canceling out chemotherapy, radiation, and normal immune system efforts.

NF-kappa B, Bcl-2 proteins, FLIP, XIAP, p53, DR5, AKT, etc. these are vital cellular components of the intricate apoptotic machinery that determines whether chemotherapy and/or your immune system will be able to eliminate cancer. And in many cases "resistance" doesn't mean flushing is impossible, it just means flushing is finicky, difficult, or that the machinery has been stressed by past exposure into the wrong position.

For example, NF-Kappa B could be like the flapper on the bottom of the tank. If it is stuck shut the tank won't flush. Or if it is stuck open, the tank will keep running and never fill - still no flush. And although many "standard" chemotherapy regimens kill a high percentage of the cancer cells (via the intrinsic pathway), they actually cause resistance in remaining cells by forcing NF-Kappa B to be stuck in the nucleus (constitutive NF Kappa-B). That is good for some cells (macrophages) but bad for other cells (AML Stem Cells).

And the Bcl-2 proteins could be like the float. If the float is adjusted wrong, the tank will never fill up with the correct amount of water. No matter that TRAIL is flipping the lever, the float was fighting against the water and there is just not enough volume to cause a flush.

Fix and Use the Pathways: New therapies are under development that target these pathways. But while we "wait" for medical science to isolate and test injectable drugs, there already are natural remedies (teas, spices, etc.) that have potent effect on these pathways. There are natural remedies that "adjust the float" so the tank can fill, and "fix the flapper" so the tank will flush. There are natural remedies to make the lever work better, to shorten or lengthen the chain, remove obstacles to the drain, etc. For example: EGCG compensates for Bcl-2 problems, Curcumin adjusts PI3K/AKT signaling and NF-Kappa B, Honokiol "fixes" FLIP, etc.

So there are many studies that show how natural remedies can enhance chemotherapy and radiation by removing resistance to apoptosis. However, if you are removing resistance to apoptosis, actually you are already removing one of the primary causes of cancer malignancy. Then why not also naturally stimulate the immune system, triggering mass apoptosis. Make the body produce extra levels of cytokines (TRAIL) to do just that. Mimic research examples. Compensate for the defects, "flip the lever", and you get a good flush.

Tricky Flush: Here are some theoretical challenges I see in using oral supplements to compensate for apoptotic defects while simultaneously modulating NK cells, macrophages, T-Cells, etc. to trigger apoptosis:
#1) To find the proper level of "compensation". For example - if a certain level of expression of the Bcl-2 proteins is required and you over compensate with Green tea (EGCG) - could you cancel the required effect?
#2) Compensation for certain defects may be time or movement dependant - either a slowly increasing supplement level, a maintained level, or a slowly decreasing level.
#3) Different batches of cells (mutations) may have different "compensation" levels needed.
#4) Younger cells may respond differently than cells just a few days older.
#5) There may be multiple defects existing in the same set of cells requiring either different supplements, different levels, or different movements.
#6) It may be important to time "flipping of the lever" (early / late / often).
#7) Since these are "chemical" reactions, cellular PH and temperature (fever) may have an effect.
#8) Since cells in the immune system (neutrophils, etc.) can "store and release" cytokines - it would be possible to temporarily tire out the immune system.
#9) The immune system may react differently after constant exposure, temporarily "wearing out" the effectiveness of a certain supplement.
#10) Sometimes it might be good to allow a few generations of cells to multiply without supplemental exposure (to later eliminate batches of "easy to destroy" cancer cells and continue "teaching / reminding" the immune system).
#11) Sometimes it might be good to focus simply on one supplement for a week with no special immune stimulation (to kill cells that would only respond to oncogenic apoptotic stimulation without additional TRAIL).
#12) The bone marrow environment naturally inhibits apoptosis - should we mobilize stem cells first, then correct protein expressions, then stimulate apoptosis, then allow homing? (endogenous cytokine therapy?)

Jaymun's Goals. Adding complexity to Jaymun's case are multiple priorities. We are trying to
1. Keep Jaymun alive and protected from infection through his neutropenic and aplastic condition.
2. Fight Leukemia (marrow and CNS).
3. Reduce risk of secondary cancers.
4. Help repair damage from chemotherapy (especially neurological damage).
5. Help Marrow recover: Neutrophils, Leukocytes, Platelets, Red Blood.
And because this battle could very well last into many years there are secondary goals:
6. Determine which particular regimens work for:
      a. Fighting marrow leukemia
      b. Fighting CNS leukemia
      c. Neutrophil proliferation
      d. Leukocyte proliferation
      e. Red blood cell proliferation
7. Find alternative herbal regimens wherever possible, because after regular usage, the body can become "immune" or at least temporarily less responsive to herbal remedies, or have an opposite response after time.

Confusing Goals? Although the priorities above may seem conflicting, they are actually synergistic. Those same herbs that activate T-cells, macrophages, and stimulate NK cells to fight cancer are also stimulating the immune system to effectively fight viral and bacterial threats despite its weakened, low, neutropenic state. It seems natural substances and immune components have an easier time crossing the blood-brain barrier than some drugs. And the same herbs that heal and soothe the GI also provide prebiotic sugars that support beneficial intestinal organisms which in turn strengthen the immune system.

Where to start? There are hundreds of natural supplements that affect elements of apoptosis in various cancers. To find a starting point, I searched the peer-reviewed journals (through scholar.google.com) for novel apoptosis related supplements discovered in the past years - then followed links, similar methods and keywords relating to apoptosis pathway elements to assemble a list of supplements that had at least in vitro (preferably in-vivo) success against leukemia and AML in particular. Then, since obviously Jaymun can't take everything at once, I started with the supplements that I can reliably source from trustworthy companies.

Dosage and plan? I must say that I originally saw oral administration of herbal remedies as posing a major challenge in bioavailability and blood plasma levels. However I now believe there are actually huge benefits to oral/GI supplement administration as opposed to IV drug delivery. Digestive differences, and variances in the ability to clear blood levels (by the liver) are actually helpful in creating a random "wave effect" where the rising or falling levels of one supplement are met with the waves from other supplements and also waves of immune stimulation and cytokine production.

I suppose you could plot the curves, and the beautiful part is, the point which the curves intersect - the "sweet spot" for apoptosis for a certain batch of cells might be different from the rest. So as several waves progress and an ascending curve slides against a descending one, you might achieve a sliding "sweet spot" that could wipe out a much larger population of cancer cells than if you achieved "instant" plasma levels by injecting a drug, and only experienced the back end of the curve as the liver cleared the substance.

Mimic Diet. Even in "healthy persons" cellular mutations occur and are eliminated by the immune system. The best way for all of us to ward off malignant cancer is to have a liberal diet of unadulterated fruits, vegetables, grains, eggs, and dairy products. That healthy diet would be somewhat random in nature to assist the body in triggering apoptosis in various unique cellular conditions. Consequently, I proposed that that the most effective method to treat cancer while "doing no harm" is to identify the key cancer fighting components of those foods and then devise a somewhat random regimen that would send intense waves of "corrective" supplements followed by waves of immune boosting supplements, and also those supplements that contribute intrinsic stress and are directly toxic to cancer cells.

Thank God. God has designed some wonderfully complex and effective substances to help our bodies handle challenges. It is more effective / less messy to find the right tool and leverage the system in place. Flipping the lever like crazy will not work if the chain has fallen off. And it makes no sense to dump buckets of chemo in the bowl and flood the place, only to discover we should just have unplugged the drain and performed a simple flush.

That is what we attempted in August and September, and it worked both times against refractory, relapsed, congenital AML (m5) that had already resisted six rounds of chemo/conditioning, a bone marrow transplant, and months of intrathecal chemo.

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