MORE INSIGHT IN THE SECOND LAW:  PLEASE READ

Authors: Rhonda M. Perciavalle, Joseph T. OpfermanSee Affiliations

Summary

BCL-2 molecules are regulators of programmed cell death Defects in this pathway contribute to human diseases. One family member, MCL-1, is unique because its expression is tightly regulated and it is essential for promoting the survival of a myriad of cellular lineages. Additionally, MCL-1 promotes the maintenance of normal mitochondrial morphology and energy production. Dissection of these functions revealed recently that they depend on separate mitochondrial sublocalizations. MCL-1's antiapoptotic activity is restricted to the outer mitochondrial membrane (OMM), whereas its function in mitochondrial physiology requires localization to the matrix. These findings provide an attractive model for how MCL-1's diverse functions may contribute to normal cell homeostasis and function. MCL-1 is highly amplified in human cancer, suggesting that these functions may contribute to malignant cell growth and evasion of apoptosis.

Keywords

apoptosis; MCL-1; homeostasis; mitochondrial function; cancer; development

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THIS IS A SUMMARY OF AN ARTICLE FROM "TRENDS IN CELL BIOLOGY".
FOR MORE INFORMATION, PLEASE GO TO THE SOURCE.
WE ARE TRACKING SUPPORTIVE MATERIAL THAT REENFORCES OUR ASSUMPTIONS!
OUR ASSUMPTIONS STILL ARE THAT MEDICATIONS THAT AFFECT THE ACTINIC SCAFFOLDING  (MICROTUBULE/MICROFILAMENT) BYPASS THE Bcl-2 RESISTANCE.
HOW MUCH AUTOPHAGY PLAYS INTO THIS IS STILL TO BE DETERMINED.  AUTOPHAGY IS MEANT TO BE FOR CANCER SURVIVAL GLOBALLY AS A RESPONSE TO STRESS ON THE CANCER CELL.  BUT THERE COMES A POINT WHEN IT IS DETRIMENTAL AND LEADS TO NON CASPASE CELL DEATH.  OTHERS HAVE CALLED THIS (RIGHT OR WRONGLY) "NECROSIS".

STRATEGIES FOR THE CURE

Since the work of Weinberg and Hanahan, we know that despite the varieties of cancer, 6 driving forces lead to cancer cell survival.  The "Hallmarks of cancer" result from:

1.Self sufficiency in growth signals: Cancer cells escape Anoikis,  They secrete their own growth factors to achieve an autocrine stimulation.

2.Insensitivity to anti-growth signals. This is achieved by changing membranes' receptors composition and number, boosting its own global growth, and secreting Tumor Necrosis factors to tamper with surrounding cell machinery.

3.Sustained Angiogenesis, to maintain "feeding" of the new tumor mass.  This is mostly critical for solid tumors.  It is critical in tumors that bleed easily such as renal cell cancers.

4.Limitless replicative potential.  By removing stops to mass formation, natural boundary sensors which contribute to shaping organs, Telomerase activation again.

5. Suppressing or escaping Apoptosis: By using cyclins and Bcl-2 and related molecules. Shielding Mitochondria and avoiding FAS/BAX, activating loopholes routes and impairing ubiquitination of growth molecules!

6.Tissue invasion and metastasis. Here the tumor cells alter composition, nature and amount of the cell receptors and adhsions molecules, cluster of differentiation (CD), and produce Tumor growth factors (TGF) which give it growth advantage vis-a-vis the surrounding tissue.

This list is by no mean exhaustive given the variety of possible oncogene mutations.  However, when one gene is causing one of the 6 pathways, it is dubbed a DRIVER mutation for that cancer, and may have significant therapeutic importance.

This 6 venues are made of important molecular structures that can be a Target for therapy. Researcher are combing them one by one and targeting them.  The successful experience with Multikinase therapy suggest that interrupting several points of the cascade appears beneficial.  Computer models are being developed to see if sequential attacks or coordinated combinations would be better models for future therapies.  The CRBCM is working to develop such a model. Our model will be complete after we enumerate all laws of nature (see our related series).

Model of cures should embrace these 6 venues in a mathematical equation...the challenge is launched!
 

ARSENIC TRIOXIDE COULD SIGNIFICANTLY EXPAND ITS ROLE IN CANCER TREATMENT. AND VITAMIN C AND MICROHYDRIN COULD COME TO THE RESCUE

Cancer cure is through death of the cancer cell.  To date, the main way of death for the cancer cell
is through Caspase activation cascade.  In most cells, we know how the main way the activation of Caspase occurs.  That is Cytochrome C is naturally anchored at the membrane inside the Mitochondria. The Anchor is in fact a chemical bonding or attachment through electrons, like molecules do attach to each other.  We believe there, Cytochrome C is attached to a Cardiolipin which is part of the lipids of the membrane.  Just imagine another molecule showing up with a free electron, the free electron could attract and pull the one involved in the attachment and break free the Cytochrome C.  That Cytochrome C electron no longer attached comes out and activates the Caspase (mostly Caspase 9 which eventually activates members of its family) and there starts the Caspase its work to coagulate DNA and genes start breaking,  thus leading to cancer cell death.  One of the molecules that produce such disturbing free electrons is Arsenic Trioxide.  This delivery of free electrons by arsenic trioxide is not limited to the mitochondria.   It occurs through the cytosol (liquid milieu of the cell) disrupting many cellular pathways, delivering global intracellular disruption.  ( for those savvy people, do remember that the " breaking" of the anchor could be induced from outside the Mitochondrial membrane through the AKT or Bax effect- this is where Bcl-2 negative effect is the strongest ) arsenic trioxide

This global disruption has been established to treat Acute Promyelocytic Leukemia (APL)  (by the way, Chinese researchers lead the way on this one).  Frankly speaking, this "Global disruption"can be used in any cancer.  The problem is that it can occur in any cell, including our normal cells.  Giving caution to the amount you use because of a narrow safety index. 

Vitamin C and Microhydrin have also free electron, that is why they can cool down free radicals and therefore are called Anti-Oxydants . The free electrons of these compounds seem to add to those of Arsenic Trioxide to Increase toxicity to the cancer cell.   It is worth mentioning that, at the DNA level, these free electron break the strand, triggering our first law (activation of P53 and stoppage of cell cycle).

3 main problems

1. Good and bad pathways are stopped, mitigating the effects of global destruction.
2. (non selectivity) Good and bad cells are killed. This effect is worse in patients with poor reserve of free electron clearing molecules (Gluthatione based, Superoxide based and others).  (CAUTION TO EVERYONE)
3. Arsenic is hard to get rid of, and chronic exposure signs will result.

But frankly speaking, you can use this to kill any Cancer.  Research will continue at CRBCM no matter what!

Of Note: Use of this information outside of the topic discussed herein, is not endorsed by the CRBCM

Understanding the Laws of Biology

IMPORTANCE OF UNDERSTANDING BIOLOGIC LAWS

With every research performed around the world, scientists learn a little more.  It is important that research focuses on a particular molecule and its interactions, specificity and efficacy. Point location research should be understood within a general plan of advances in biomolecular research.  To find that, TGF Beta, when produced, will make a cancer grow and therefore make the cancer more resistant to treatment, is nice. It adds to the detailed knowledge.  TGF(s) act on membrane receptors, therefore it will harvest the signal pathways to display its might.  We know that it will reach or may emanate from some transcription genes.  The tract its actions have to follow to affect the cell is full of loopholes and pitfalls.  Going after TGF(s) should be part of a planned combination approach.  It cannot work in over 30% of the people because of genetic heterogeneity which in itself is nature's protection for host survival.

Here at CRBCM, we understand that to cross the 50% effectiveness, our current treatment strategies must include the activity of the 2nd law well described here.  And better yet the first 2 laws.  Disruption of gene, and that of Microtubule that will lead to caspase release (Cytochrome c disruption implied).  Membrane based effects are only as good as they are able to involve an increased activity of fas and Bax.  Short of that, they are 70% ineffective.  (You can't discount 30% though)

TGF could present an opportunity for treatment.  We made an early allusion to the JUDO.  Use the power of the attacker to send him to the floor "in the general direction of his attack".  TGF wants to achieve acceleration of growth and cellular multiplication.  Disruption of gene and microtubule may in fact be more effective when faster multiplication is achieved? This is risky, but not a crazy a approach.  That is also why chemotherapy works only on dividing cells!

Globally, however, TGF and Bcl-2 tend to protect cancer cell. TGF seems to give a growth advantage to cancer cells vis-a-vis surrounding cells.  Bcl-2 seems rather to be a protection mechanism from reaching the mitochondrial Caspase,  protecting therefore cancer cell from Apoptosis, the cure to cancer. 
With this background info, we can now judge any research coming along as to its importance, and see how it fits in the general strategy to achieve the cure we all want.

Apoptosomes

Apoptosomes: engines for caspase activation.

Adams JM, Cory S.

Source

The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3050, Victoria, Australia. adams@wehi.edu.au

Abstract

"Activation of the caspases that initiate apoptosis typically requires cognate scaffold proteins, including CED-4 in Caenorhabditis elegans, Apaf-1 in mammals and Dark in Drosophila. Each scaffold protein oligomerizes procaspases into a complex called the apoptosome, but the regulation and biological roles of the scaffolds differ. Whereas CED-4 is restrained by the Bcl-2 homologue CED-9, Apaf-1 is inhibited by its WD40 repeat region, until it is activated by cytochrome c, derived from damaged mitochondria. Although Dark also has a WD40 region, its activation does not seem to involve cytochrome c. CED-4 is essential for apoptosis in the worm and Dark for many apoptotic responses in the fly, but the Apaf-1/caspase-9 system probably amplifies rather than initiates the mammalian caspase cascade."
 (end of abstract)
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This research further confirms the path of the second law driving the forces down the cascade of events
starting with Microfilament/Microtubule disturbance or destruction.  The author clearly feels that once the
Apaf-1/Caspase-9 system is initiated, it amplifies its action leading to apoptosis.  Mention of the Bcl-2 (or other molecules comparable) is critical because it is the main barrier to full display toward apoptosis.  Last point :the Caspases are also a family of enzymes/protein based structure/meaning the potency to achieve Apoptosis varies.

Apaf-1 is Apoptotic Protease-activating Factor-1, a key factor in the cascade to Apoptosis.  I should also stress that this factor is more concentrated in liver, spleen, kidney and brain. Tissues where primary tumors are the toughest to treat.  Therefore, targeting this enzyme for activation could drive up Apoptotic cascade or cell death.

Of note, people in full inflammatory process with increased TNF have a mitigated result when it comes to Apoptosis because TNF also stimulate NF-kB which has anti-apoptotic trends.  Unless it chooses to go down the path of death-domain signaling way (Fas) or stimulate MAPK pathway which is more pro-apoptotic.   ARE PEOPLE WITH AUTOIMMUNE DISEASE POOR RESPONDERS TO TAXOL BASED CHEMOTHERAPY BECAUSE OF THIS?  SHOULD WE BE TESTING ANA AND LEVEL OF TNF (Tumor Necrosis Factor) TO GAGE RESPONSE TO THERAPY?

CRBCM today: Further evidence of 2nd law of nature

Further evidences of 2nd law of nature/CRBCM

If you compromise Cell divison, the cell will need to be destroyed
one thing is for sure.  DNA Breakage and mistakes or mismatches lead to cell cycle arrest (First law).  What is interesting is that the second law is very much linked to this. Once the repair occurs, a number of peri microtubular reactions need to occur to relieve that arrest and allow continuation of the mitosis.  This is the connection to the second law.
Also as we are further looking into this matter, we are finding further evidence that there is an intricate connection between Microtubule and Mitochondria.   Even the location of Mitochondria is not random and seems linked to the integrity of the filamentous connection.  We are learning about Nuage and Mitochondrial Cement.  The further we look, the more we can now ascertain the existence of the 2nd law.
We are also learning, that not all the antikinesin are the same.  Some are not as important, affecting peripheral molecules, but some involve the location of the "consensus sequence", and may be more important.

We also are learning that Cyclin ubiquitination and therefore destruction could be exacerbated by perimicrotubular disturbances.  Is this the mechanism of bypassing BCL-2 resistance?  More light is needed.

We will let you know what we find at CRBCM.

Sons of the Sevenless

SONS OF THE SEVENLESS/Hypothesis for cancer Research

As we move forward here at CRBCM, we are increasingy  fond of one line of molecules;
first because of their name, and because we believe that their inhibitors could be the answer to the resistance
to some of the medications already in our armamentarium, namely Avastin,  Imatinib and Herceptin.  We believe that the Sons of The Sevenless which are regulator molecules switching on RAS would break resistance to Tyrosine Kinase resistance.  Sons of the Sevenless, what a name!  But don't you remember they say: "KILL THE SWITCH" AND DARK WILL COME.   THE SWITCH IS THE SONS OF THE SEVENLESS...BASAL CELL CANCER OF THE BREAST, THE CRBCM IS AFTER YOU...SINCE THE SUGGESTION THAT BASAL CELL CANCER OF THE BREAST IS LIKE OVARIAN CANCER BY ITS GENOME.  MARK MY WORD: KILLING THE SONS OF THE SEVENLESS OR KILLING THE SWITCH IS THE KEY TO TREATMENT.

ADDING TAXANE (or better yet an Anti-Kinesin) AFTER KILLING THE SWITCH (SONS OF THE SEVENLESS) WILL TURN ON THE MITOCHONDRIAL CASPASE BY AN INHERENT REFLEX MECHANISM WHICH WILL BYPASS BCL-2.  THAT'S HOW YOU LEAD TO CANCER CURE!

OH BY THE WAY,  ADDING STELAZINE TO AVASTIN MAY JUST DO THE TRICK FOR RECURRENT BRAIN TUMORS TOO. IT IS AN ANTI-CALMODULIN AFTER ALL!

RESEARCH IS ON AT CRBCM.