Search This Blog

Wednesday, August 20, 2008

The Calcium Gate Hypothesis of Cancer

In 1978 I was finishing my Masters in Public Health at the University of Michigan School of Public Health. I had fallen under the spell of Dr. Bruce Chin who was enthusiastically studying the mechanisms of carcinogenesis. I took his advanced class in understanding the cellular mechanisms of cancer three times. During this time, I also developed my ideas that there must be a crucial switch that turns this cancerous process on and off and that the most likely candidate for this switch was an as yet unknown calcium gate that could be controlled by phosphorylation and dephosphorylation. This gate would be analogous to the then known cardiac gate controlled by phospholamban, which was discovered by Dr. Madeleine Kirchberger at the Mount Sinai School of Medicine in New York. I wrote this hypothesis into a paper that I submitted to the Journal of Theoretical Biology, but it wasn’t accepted for publication.

Ironically I came to New York in 1979 and later found myself working in Dr. Kirchberger’s lab on a project to isolate and purify phospholamban, but phopholamban is a membrane bound protein that was more difficult to purify than we initially thought and since I couldn’t reproduce my initial results, I had to drop this project and start a new project for a Ph.D. thesis. However, I very much admired the rigorous research integrity and intensity of Dr. Kirchberger’s lab and I learned a great deal about phospholamban and calcium signaling in the heart. I was still convinced that there must be a connection between the uncontrolled cell division in cancer cells and the control of the calcium gate in normal cells. I discussed this idea with many scientists because I wanted to find someone who was working in this area, but it still needed much more development to become a mainstream idea.

Years passed and I periodically scanned the literature to see if there had been more thought about the calcium gate hypothesis and cancer. The cancer field seemed to take off in the direction of a balance between kinase and phosphatase control of the cell’s metabolic machinery. This seemed to be promising since I had thought that the calcium gate would be controlled by the kinase and phosphatase molecules. The calcium field seemed to have its own direction and developed into an important field of research focusing on the myriad number of enzymes and kinases controlled by calcium signals. However, there didn’t appear to be a direct connection made between a particular kinase/phosphatase pair that were crucial in controlling a start/stop point in cell division.

This has now begun to change and suggests a redox sensitive switch -see:

http://www.ncbi.nlm.nih.gov/pubmed/18377233?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/17168752?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/18544350?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/18372105?ordinalpos=20&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/18671159?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/18466777?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


Is it just coincidence that oncogenes and calcium control genes are near each other? The following list contains searches for oncogenes that happen to appear near to calcium control genes (clicking on the links give GOOGLE searches for the oncogene and the calcium gene and cancer):


27
Hs
ABL2
v-abl Abelson murine leukemia viral
oncogene homolog 2 (arg, Abelson-related
gene)
1q24-q25


777
Hs
CACNA1E
calcium channel, voltage-dependent,
alpha 1E subunit
1q25-q31

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%221q24-q25%22+1q25-q31&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



208
Hs
AKT2
v-akt murine thymoma viral oncogene
homolog 2
19q13.1-q13.2

773
Hs
CACNA1A
calcium channel, voltage-dependent,P/Q type, alpha 1A subunit
19p13.1-p13.2


51476
Hs
CABP3
calcium binding protein 3
19q13.33

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2219q13.1-q13.2+%22+19q13.33&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



867
Hs
CBL
Cas-Br-M (murine) ecotropic retroviral
transforming sequence
11q23.3

57010
Hs
CABP4
calcium binding protein 4
11



781
Hs
CACNA2D1
calcium channel, voltage-dependent,
alpha 2/delta subunit 1
7q21-q22
673
Hs
BRAF
v-raf murine sarcoma viral oncogene
homolog B1
7q34

674
HsBRAFP
v-raf murine sarcoma viral oncogene
homolog B1 pseudogene
7q34

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%227q34+%22+7q21-q22&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


12298
Mm
Cacnb4
calcium channel beta 4 subunit
2 33.9 cM
12170
Mm
Bmyc
brain expressed myelocytomatosis
oncogene
2


782
Hs
CACNB1
calcium channel, voltage-dependent,
beta 1 subunit
17q21-q22
1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3



54245
Rn
Crk
v-crk avian sarcoma virus CT10 oncogene
homolog
10
783
Hs
CACNB2calcium channel, voltage-dependent,
beta 2 subunit
10p12

12296
Mm
Cacnb2
calcium channel beta 2 subunit
2 14.5 cM

12298
Mm
Cacnb4
calcium channel beta 4 subunit
2 33.9 cM

12170
Mm
Bmyc
brain expressed myelocytomatosis
oncogene
2



773
Hs
CACNA1A
calcium channel, voltage-dependent,
P/Q type, alpha 1A subunit
19p13.1-p13.2

1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2217p13.3+%22+19p13.1-p13.2&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



775
HsCACNA1C
calcium channel, voltage-dependent, L
type, alpha 1C subunit
12p13.3
1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2217p13.3+%22+12p13.3&as_q=cancer&btnG=Search%C2%A0within%C2%A0results

778
Hs
CACNA1F
calcium channel, voltage-dependent,
alpha 1F subunit
Xp11.23
867
Hs
CBL
Cas-Br-M (murine) ecotropic retroviral
transforming sequence
11q23.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2211q23.3%22+Xp11.23&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



8911
Hs
CACNA1I
calcium channel, voltage-dependent,
alpha 1I subunit
22q13.1

1399
Hs
CRKL
v-crk avian sarcoma virus CT10 oncogene
homolog-like
22q11.21

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2222q11.21%22+22q13.1&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


782
Hs
CACNB1
calcium channel, voltage-dependent,
beta 1 subunit
17q21-q22

1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2217p13.3%22+17q21-q22&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


12295
Mm
Cacnb1
calcium channel beta 1 subunit
11 58.0 cM
12928
Mm
Crko
avian sarcoma virus CT10 (v-crk)
oncogene homolog
11 44.15 cM

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2211+44.15+cM%22+11+58.0+cM&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


1436
Hs
CSF1R
colony stimulating factor 1 receptor,
formerly McDonough feline sarcoma viral
(v-fms) oncogene homolog
5q33-q35
Links309
Hs
ANXA6
annexin A6
5q32-q34



776
Hs
CACNA1D
calcium channel, voltage-dependent, L
type, alpha 1D subunit
3p14.3

1894
Hs
ECT2
epithelial cell transforming sequence 2
oncogene
3q26.1-q26.2

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%223q26.1-q26.2%22+3p14.3&as_q=cancer&btnG=Search%C2%A0within%C2%A0results

12291
Mm
Cacna1g
calcium channel, voltage-dependent, T
type, alpha 1G subunit
11
13649
Mm
Egfr
epidermal growth factor receptor
11 9.0 cM


12295
Mm
Cacnb1
calcium channel beta 1 subunit
11 58.0 cM

13649Mm
Egfr
epidermal growth factor receptor
11 9.0 cM



24329
Rn
Egfr
Epidermal growth factor receptor, formerly
avian erythroblastic leukemia viral (v-erbB)
oncogene homolog (Erbb1)
14

12289
Mm
Cacna1d
calcium channel, voltage-dependent, L
type, alpha 1D subunit
14 8.0 cM

54234
Rn
Cacna1e
calcium channel, voltage-dependent, L
type, alpha 1E subunit



2002
Hs
ELK1
ELK1, member of ETS oncogene family
Xp11.2

778
Hs
CACNA1F
calcium channel, voltage-dependent,
alpha 1F subunit
Xp11.23

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=Xp11.2+Xp11.23&as_q=cancer&btnG=Search%C2%A0within%C2%A0results

Monday, August 18, 2008

A Creative Financial Fix to the Mortgage Crises?

Rick Santelli of CNBC (see - http://www.cnbc.com/id/15837966/) suggested that we create an opportunity for young home buyers to purchase foreclosed properties. There are pluses and minuses to such deals, but the underlying theme is that we need to create a way out of the mortgage crises. An interesting point that Rick made is that we (investors and financial institutions) must “bite the bullet” and step up to invest in new mortgage backed instruments. As a small investor, I agree that investors should invest some of their money to promote the greater good. However, this is sometimes difficult to see and reconcile with the capitalist creed to make money...

How to turn the mortgage crises around so that we have a win-win scenario? Perhaps there could be a way to interest REITs in the housing market if the offer was too good to ignore? Fannie and Freddie are sitting on large amounts of federal aid that are becoming more difficult for home buyers to access. If existing or new REITs could access these funds to buy, rent and sell homes, then perhaps we could create a creative way forward out of the current mortgage crises.

Thursday, August 14, 2008

Active and Inactive Receptor States

When we write the set of brackets around a chemical species to represent a chemical concentration, it really represents a sum of probable chemical species that are grouped together. This is especially important when we consider the potential states of large protein molecules such as cellular receptors. In pharmacologic theory, we often characterize the active or inactive states of the receptor as initial quantities such as [R] and [R*]. This is convenient for mathematically manipulating these receptor states in order to derive information about how they behave in the presence of stimulating or inhibiting molecules such as agonists or antagonists, but conveys little about the underlying molecular species connected with these active and inactive states.

Even using specific and detailed molecular dynamic simulations, the meaning behind the [R] and [R*] receptor states becomes less clear when we explicitly model these states. Since there are a vast multitude of possible conformations, it becomes increasingly difficult to separate out those conformations that belong to the active or inactive receptor states. Ironically, this has brought us full circle to consider what [R] and [R*] represent as specific molecular species. The closer we are to understanding the details of these states from crystallographic structures, the further we are from understanding the molecular species that make up the active and inactive states.

Anyone who has truly studied pharmacologic theory and molecular modeling knows that we often wind up with this essential conundrum. Some have chosen particular molecular motions or interactions such as the breaking of a salt bridge or the twist or turn of a helix to describe what they think is the active receptor state. These descriptions may contain accurate descriptions of the active receptor state, but the fact that receptors exist in a sea of thermal noise and that activating drugs or ligands bind to their target receptors with only a 3-4 kcal/mol maximum energy difference and display different active molecular conformations suggest that we need a clearer on and off molecular switch for receptor activation.

These are not impossible physical constraints to accommodate in a biophysical molecular model for receptor activation (see - http://www.bio-balance.com/JMGM_article.pdf and http://www.bio-balance.com/GPCR_Activation.pdf ), but because receptors are complex molecular structures that exist in multiple domains, the teasing apart of the essential molecular signal is very difficult from both an experimental and theoretical perspective. This is particularly true if the biophysical models fail to accommodate major experimental findings such as the redox sensitivity of receptor systems or the reduction in desensitization by combining an antagonist with an agonist. A comprehensive molecular model for receptor activation should contain these findings.

Wednesday, August 13, 2008

Calling for Pharmacologists, Cell Biologists and Those Working in Cellular Signaling

Calling all pharmacologists, cell biologists and those working in cellular signaling to test agonist/antagonist combinations for their ability to reduce or prevent receptor tachyphylaxis, desensitization or tolerance. It is important to the field of pharmacology that the simple act of combining an antagonist with an agonist reduces receptor desensitization be independently tested. Those with suitable experimental systems that demonstrate receptor desensitization, tachyphylaxis or tolerance should consider testing agonist/antagonist combinations against the responses observed with the agonist alone.

Saturday, August 9, 2008

Why Agonist/Antagonist Drug Combinations Work

At the most fundamental level, the reason that adding an antagonist to an agonist in a specific ratio greatly reduces or eliminates receptor desensitization is that the dynamic competition between the agonist and the antagonist allows the receptor to function with little or no desensitization. What this means is that by slightly inhibiting the receptor, we can make sure that it doesn’t become overly excited and desensitized by the agonist drug alone.

What’s unique about this is that we can calculate the optimal ratios of agonist and antagonist to create the effects we want from the stimulated receptors. This hasn’t been accomplished before, because the importance of the agonist/antagonist ratio on receptor desensitization has gone unnoticed. Although there is some initial progress is this area, especially by Richard Bond (see - http://tinyurl.com/5kexhe, http://tinyurl.com/66oce8, http://tinyurl.com/6yhvgv and http://tinyurl.com/6plywh), the idea that we can create useful agonist/antagonist combinations to reduce or prevent desensitization, tachyphylaxis or tolerance has been slow to enter current pharmacological thinking.

This may seem surprising since our patented and published works were the first to describe how to make and control such agonist/antagonist combinations to achieve desired effects such as reducing or preventing receptor desensitization (see - http://tinyurl.com/6744mr, http://tinyurl.com/5ahxgm, http://tinyurl.com/5z8an6 and http://tinyurl.com/5mpsf7). Although this body of work has been ignored by many subsequent researchers, our priority dates on our patent filings certify our claims to first to discover this important means of modification of the receptor response.

Wednesday, August 6, 2008

Ideas About Anthrax

Ideas are a dime a dozen, but when one of my suggestions are followed, it is heartening. As I grow older, I value the effort that must be expended to follow through with what we like to call “good ideas”. Those who follow through and test these good ideas are the unsung heroes of scientific research and development. That said, I had previously e-mailed the following suggestions to the federal authorities on the dates below:

11/2/01
With regard to tracing the source of the anthrax. Cross contamination of overseas postoffices and other mail may help to determine where the anthrax entered the global mail system. It seems to me that by cross checking databases listing laboratory personnel (such as the Lists of World Culture collections: http://wdcm.nig.ac.jp/hpcc.html) who are capable of producing anthrax with other databases listing terrorist sympatizers and extreme right fanatics such as the Tim McVeigh sympathizers, that we could narrow down the search to possibly a few hundred places where appropriate personnel could question people and take appropriate samples to determine if the strains match.

7/14/02
Efficacy Corporation
30 West 86th Street - 1B
New York, NY 10024
(212) 769-3877 * biobalance@aol.com * Fax. (212) 769-3877

In order to find the suspect who carried out the anthrax attacks may I suggest that a scientific approach may work best. The method would require the hepa vacuuming of a suspect's clothes, car, home, etc. Anywhere the anthrax spores may have been. This should obviously be done with a clean filter, then the samples should be divided into at least two to three groups. One group should be cultivated under conditions that favor the germination of the anthrax spores and if found, they should be compared to the strains sent to the Senators' offices. Another sample should be pretreated to kill everything but spores, and then cultivated and examined for the same strain as was used in the attacks. The third should be examined microscopically to determine if the spores are present.

In addition, any filtering devices from the suspects' living or working quarters should be examined by the methods given above.

This will take time, but may be the best evidence to definitively convict the person of the crime.

Sincerely,
Richard Lanzara, PhD
President & Chief Scientist
Efficacy Corporation

Monday, August 4, 2008

Dick Cheney and the Oil Executives

Over the past year oil has doubled in price yet industry reports show some companies reporting a decrease in oil production. We all know that we’re in a period of financial adjustment and pain. Personally, I’m waiting for Dick Cheney to reconvene his energy executive meeting that took place early in President Bush’s first term and provide new leadership for a sane energy policy. There’s still time.

Sunday, August 3, 2008

My Discovery

Since filing my first patent on September 30, 1992 (see - http://www.freepatentsonline.com/5597699.html), those who do not understand pharmacological theory want to understand what it is that I’ve discovered. My discovery has been that by combining agonist (or activating) drugs with antagonist (or inhibiting) drugs in specific ratios we can modulate the dose-response relationship to achieve whatever effect we want. This means that we can design new drug combinations that work better than the agonist (or activating) drugs alone. This is a potentially huge market as these drugs comprise roughly more than 30% of all drugs currently being sold. My unique contribution is that by combining drugs, we achieve beneficial effects without having to design new molecular drug entities. These drugs are already on the market and have been FDA approved so their actions and side effects are well known. By using these specific drug combination ratios, we can create safer and more effective drugs now if only we had more interest from the investment community.