Aa
Selective and Therapeutic Elimination of Cells that Produce HBV
http://webserver.health.state.pa.us/pdf/cure/2010-2011/institute%20of%20hepatitis%20&%20virus%20research/2010%20grant%20annual%20progress%20report%20sfy10%20ihvr.pdf
Project Overview
The overall goal of this project is to advance a new method of managing chronic hepatitis B
virus (HBV), with the ultimate goal of human use. Specifically, we will determine if drugs that
selectively kill HBV infected cells in tissue culture, can be used safely and effectively in
animals. We have determined that two drugs, a statin (atorvastatin) and a polyketide
(meclocycline/demeclocycline), already known to be safe in people, are much more toxic to
HBV producing cells in culture than they are to uninfected cells. We must now determine if
there are better drugs in those classes for our purposes. This study will identify a compound with
the best profile for selective cell elimination. The deliverable at the completion of this initial
study will be the identification of a drug that is ready to be moved from tissue culture to future
animal studies.
Project Overview
The overall goal of this project is to advance a new method of managing chronic hepatitis B
virus (HBV), with the ultimate goal of human use. Specifically, we will determine if drugs that
selectively kill HBV infected cells in tissue culture, can be used safely and effectively in
animals. We have determined that two drugs, a statin (atorvastatin) and a polyketide
(meclocycline/demeclocycline), already known to be safe in people, are much more toxic to
HBV producing cells in culture than they are to uninfected cells. We must now determine if
there are better drugs in those classes for our purposes. This study will identify a compound with
the best profile for selective cell elimination. The deliverable at the completion of this initial
study will be the identification of a drug that is ready to be moved from tissue culture to future
animal studies.
other info about oubain.looks like the same old story, old cheap drugs with no patents or not patentable are made out of market.......
http://www.infarctcombat.org/heartnews-17.html
http://fourfoldhealing.com/strophanthus/
http://www.infarctcombat.org/heartnews-17.html
http://fourfoldhealing.com/strophanthus/
http://www.phoenixbiotechnology.com/documents/CGs%20and%20heart%20health%202012.pdf
Cardioactive glycosides exert positive inotropic effects on
cardiomyocytes through the inhibition of Na+
/K+
-ATPase. We
showed previously that in human hepatoma cells, digoxin
and ouabain increase the rate of the mevalonate cascade and
therefore have Na+
/K+
-ATPase-independent effects. In the
present study we found that they increase the expression and
activity of 3-hydroxy-3 methylglutaryl-CoA reductase and the
synthesis of cholesterol in cardiomyocytes, their main target
cells. Surprisingly this did not promote intracellular cholesterol
accumulation. The glycosides activated the liver X receptor
transcription factor and increased the expression of ABCA1 (ATPbinding cassette protein A1) transporter, which mediates the efflux
of cholesterol and its delivery to apolipoprotein A-I. By increasing
the synthesis of ubiquinone, another derivative of the mevalonate
cascade, digoxin and ouabain simultaneously enhanced the rate
of electron transport in the mitochondrial respiratory chain and
the synthesis of ATP. Mice treated with digoxin showed lower
cholesterol and higher ubiquinone content in their hearts, and
a small increase in their serum HDL (high-density lipoprotein)
cholesterol. The results of the present study suggest that
cardioactive glycosides may have a role in the reverse transport
Cardioactive glycosides exert positive inotropic effects on
cardiomyocytes through the inhibition of Na+
/K+
-ATPase. We
showed previously that in human hepatoma cells, digoxin
and ouabain increase the rate of the mevalonate cascade and
therefore have Na+
/K+
-ATPase-independent effects. In the
present study we found that they increase the expression and
activity of 3-hydroxy-3 methylglutaryl-CoA reductase and the
synthesis of cholesterol in cardiomyocytes, their main target
cells. Surprisingly this did not promote intracellular cholesterol
accumulation. The glycosides activated the liver X receptor
transcription factor and increased the expression of ABCA1 (ATPbinding cassette protein A1) transporter, which mediates the efflux
of cholesterol and its delivery to apolipoprotein A-I. By increasing
the synthesis of ubiquinone, another derivative of the mevalonate
cascade, digoxin and ouabain simultaneously enhanced the rate
of electron transport in the mitochondrial respiratory chain and
the synthesis of ATP. Mice treated with digoxin showed lower
cholesterol and higher ubiquinone content in their hearts, and
a small increase in their serum HDL (high-density lipoprotein)
cholesterol. The results of the present study suggest that
cardioactive glycosides may have a role in the reverse transport
this drug oubain is too dangerous and cannot be used if not strickly monitored by expert docotrs.
remains to be seen which dose can make 0.016uM Oubain in the liver and if it an extremely safe dose
http://www.wisegeek.com/what-is-ouabain.htm
Ouabain, also called g-strophanthin, is a treatment for heart failure and problems with the atrium. Though it is not widely used, doctors that prescribe this treatment indicate that it is particularly effective, increasing heart function without endangering the heart through rapid heart rate or high blood pressure. Its use in human patients is limited to France and Germany, though the medication is used in studies in other parts of the world. Historically, ouabain has been used as a poison.
Ouabain is found in vines endemic to regions in Africa and Asia. People inhabiting regions where ouabain can be found frequently use the substance as a poison that, when applied to arrow heads or the tips of spears, causes cardiac arrest in animals. The poison can enter the bloodstream through small cuts, so even an arrow that merely grazes an animal can deposit enough poison to cause death.
The chemical in ouabain works by increasing the amount of sodium that is drawn into the cellular membrane. This increase results in an increase in calcium in the cells which make the heart beat more strongly. While large doses of this chemical can result in death, small doses can increase cardiac function without putting a patient at any risk. The chemical can be used to treat cardiac disorders, including heart failure and fibrillation, or flutter, of the atrium.
Ouabain, also called g-strophanthin, is a treatment for heart failure and problems with the atrium. Though it is not widely used, doctors that prescribe this treatment indicate that it is particularly effective, increasing heart function without endangering the heart through rapid heart rate or high blood pressure. Its use in human patients is limited to France and Germany, though the medication is used in studies in other parts of the world. Historically, ouabain has been used as a poison.
Ouabain is found in vines endemic to regions in Africa and Asia. People inhabiting regions where ouabain can be found frequently use the substance as a poison that, when applied to arrow heads or the tips of spears, causes cardiac arrest in animals. The poison can enter the bloodstream through small cuts, so even an arrow that merely grazes an animal can deposit enough poison to cause death.
The chemical in ouabain works by increasing the amount of sodium that is drawn into the cellular membrane. This increase results in an increase in calcium in the cells which make the heart beat more strongly. While large doses of this chemical can result in death, small doses can increase cardiac function without putting a patient at any risk. The chemical can be used to treat cardiac disorders, including heart failure and fibrillation, or flutter, of the atrium.
Figure 1: Oubain appears to be selectively toxic to HBV producing cells. The liver tissue cancer
cell derived line Huh7, was engineered such that it produces HBV when tetracycline is removed
from the culture medium. In this way, the effect upon cell growth of various drugs, such as
Oubain (shown here, in Figure 1A.) can be evaluated under conditions where the only apparent
difference between the cells is tetracycline and the production of HBV. At 0.16 uM, Oubain has
little effect upon the growth of these cells when HBV is not produced (tet on, less than 20%
cytotoxicity). However, in the presence of even 0.016uM Oubain, as much as 60% of the cells
are killed, when HBV is produced.
cell derived line Huh7, was engineered such that it produces HBV when tetracycline is removed
from the culture medium. In this way, the effect upon cell growth of various drugs, such as
Oubain (shown here, in Figure 1A.) can be evaluated under conditions where the only apparent
difference between the cells is tetracycline and the production of HBV. At 0.16 uM, Oubain has
little effect upon the growth of these cells when HBV is not produced (tet on, less than 20%
cytotoxicity). However, in the presence of even 0.016uM Oubain, as much as 60% of the cells
are killed, when HBV is produced.
Summary of Research Completed
The labs of Andrea Cuconatti, Ph.D., with HaiTau Guo, Ph.D. and Ju-Tau Guo, M.D., working
with trainees John Rogowosky, Mathew Campagna, and Laura Dipaulohave have determined the
following:
HBV producing cells, in culture, are consistently approximately 2-3 times more growth sensitive
to NaK ATPaseion channel inhibitors, Oubain and Oleandrin, than are congenic cells that do not
produce HBV. This is an interesting lead, since although the difference in sensitivity is small, it
is reproducible, and suggests that HBV producing cells may require a level of NaK ATPAse
activity greater than do uninfected cells. It also validates the approach. Another possibility is
that the affects of Oubain and Oleandrin are due to “off target” effects. Two strategies will be
taken from this point. The first will be to determine if other NaK ATPase inhbitors or other
structurally related compounds have similar or, hopefully, enhanced, selective HBV cell
producer killing affects against the cell systems used, to date, and other cell systems. If so, the
mechanism of action and specific viral gene products associated with the selective cell killing
will be pursued. The second strategy will be to screen a larger library compounds of selective
HBV killing.
Results could also suggest that people who are chronic carriers of HBV might have selective
sensitivity to drugs that are otherwise well tolerated by uninfected individuals.
The labs of Andrea Cuconatti, Ph.D., with HaiTau Guo, Ph.D. and Ju-Tau Guo, M.D., working
with trainees John Rogowosky, Mathew Campagna, and Laura Dipaulohave have determined the
following:
HBV producing cells, in culture, are consistently approximately 2-3 times more growth sensitive
to NaK ATPaseion channel inhibitors, Oubain and Oleandrin, than are congenic cells that do not
produce HBV. This is an interesting lead, since although the difference in sensitivity is small, it
is reproducible, and suggests that HBV producing cells may require a level of NaK ATPAse
activity greater than do uninfected cells. It also validates the approach. Another possibility is
that the affects of Oubain and Oleandrin are due to “off target” effects. Two strategies will be
taken from this point. The first will be to determine if other NaK ATPase inhbitors or other
structurally related compounds have similar or, hopefully, enhanced, selective HBV cell
producer killing affects against the cell systems used, to date, and other cell systems. If so, the
mechanism of action and specific viral gene products associated with the selective cell killing
will be pursued. The second strategy will be to screen a larger library compounds of selective
HBV killing.
Results could also suggest that people who are chronic carriers of HBV might have selective
sensitivity to drugs that are otherwise well tolerated by uninfected individuals.
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