This looks like a promising line for future research. But the study appears to have used tumor cells that were deficient in Cdk5 already. They didn't here investigate agents that might block Cdk5. We'll need to await further research to see if new therapeutic agents might be developed from this. The journal abstract seems to be here: http://science.sciencemag.org/content/353/6297/399
It frustrates me no end that journalists writing news articles NEVER provide links to the source material. Grrr.
CDK5 was disrupted in this study by short hairpin (aka small hairpin) RNA interference and by CRISPR (genome editing), neither of which have reached the point of widespread testing in clinical trials.
Interestingly there has been reason to think about "availability of potent, selective, brain permeable cdk5 inhibitors" as a treatment for Alzheimers.
http://www.ncbi.nlm.nih.gov/pubmed/12540052
Pfizer has an experimental compound called CP-681301 that inhibits CDK5, but I can't see that this has even made it to a phase I safety trial in humans.
Thanks for providing further information on the study. It's interesting that multiple agents being pursued for alzheimer's also have relevance for glioma. In both cases, crossing the blood-brain barrier is a chief obstacle in treatment. Readers of this blog will recognize several agents in this mouse alzheimer's "cocktail" that many of us use already for glioma: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014015 "Formulation of a Medical Food Cocktail for Alzheimer's Disease: Beneficial Effects on Cognition and Neuropathology in a Mouse Model of the Disease"
I'm aware of this study, and do have a copy of it. The study showed essentially two things: 1) inhibition of viability and proliferation of glioma cells at curcumin concentrations between 6.25 and 50 micromolar and 2) induction of stemness markers (CD133, nestin, etc) and stem-like behaviour at a curcumin concentration of 50 micromolar. Given that free concentration of curcumin in plasma is in the neighborhood of 100 nanomolar (500 times less than the concentration used in this study) after a single 2000 mg dose of Longvida, the relevance of this study is far from clear.
In vivo studies are always more convincing that most in vitro work, for the simple reason that any concentration of a drug can be used in vitro, while in vivo there are limits, in that the drug cannot be given at such a high concentration that it kills the animal or causes them to lose weight due to treatment toxicity.
My own theory is that curcumin is more likely to be beneficial for glioma due to effects on immune cell populations (especially via inhibition of STAT3), though I don't rule out direct effects. Curcumin can build up to much higher levels in tissues such as brain tissue than it does in plasma, though how much of this is in an unbound, active form is an open question.
Every mouse study I've seen using curcumin showing any effect led to prolonged survival, and this evidence is more trustworthy than the in vitro promotion of stemness at the unachievable (in vivo) concentration of 50 micromolar, in my opinion.
I can upload this study to the Library if anyone desires to read in full.
I uploaded 2 curcumin studies to the Library (folder 2 - preclinical therapies, curcumin subfolder). One is the study where it induced stemness in vitro at 50 micromolar. Another, in direct contrast to the first study, shows curcumin differentiating glioma initiating cells and decreasing their self-renewal at the much more reasonable concentration of 2 micromolar, and also prolonging survival in mice.
Hi Stephen, would it be possible to add a column on achievable serum levels in your non-pharmaceutical list? I'm trying to read as many articles as possible on Pubmed on every suggested supplement to make an opinion on whether or not to include it in the cocktail for my father. But both mode of action (ie what pathways etc it acts on) as well as dosing is very hard for me to interpret as I have no medical background, i.e. is a 100 uM dose at all achievable with supplement X and so on.
What I'm trying to do is compose a large Excel spreadsheet with articles pro and con each supplement and try to make a weighted opinion on whether or not to include it.
Yes, I can add a column to the list. You'll find that 99% of in vitro studies testing nutraceutical type compounds for cancer are using unrealistic concentrations. The matter is complicated by the fact that most pharmacokinetic studies report total plasma concentrations, though it is generally only the free, unbound, fraction that will be pharmacodynamically active. Additionally, metabolites of the ingested substance may also be active (or not) and add to the in vivo effect. I theorize that the mechanisms of action identified by in vitro work is likely often not the operative mechanism of action in vivo, where potential effects on immune cells, tumor vasculature, circulating factors like glucose, insulin, hormones, growth factors, etc, come into play. In vitro systems are extremely simplified compared to living organisms, which probably goes without saying.
Thanks! Yes, I've noticed that most in vitro studies seem to revolve around dosages in the tens or hundreds of micromoles. One problem being that many of the compounds seem to be hormetic with low dosages possibly being tumorpromotive, and thus my thinking goes "what if this supplement actually worsens the situation in the dosages likely to be achievable IRL"?
One study proposed a "nutrient mix" consisting of selenium, EGCG among other substances and found the mix to be tumorpreventive at >500 uM. Looking at the graphs in that study it would however seem that dosages less than that were actually tumorpromotive, unless I misunderstand. (http://www.ncbi.nlm.nih.gov/pubmed/24867464)
Another question that rises is whether some supplements are additive, synergistic or antagonistic with each other?
One study seems to point at TMZ + Curcumin + Resveratrol being highly synergistic when used together (http://www.ncbi.nlm.nih.gov/pubmed/25542083)
In the end I don't know it the supplements make much of a difference or not, but at the moment being that's the only viable option I have since the neurooncologist said strictly no to any off-label prescriptions.
This looks like a promising line for future research. But the study appears to have used tumor cells that were deficient in Cdk5 already. They didn't here investigate agents that might block Cdk5. We'll need to await further research to see if new therapeutic agents might be developed from this. The journal abstract seems to be here:
ReplyDeletehttp://science.sciencemag.org/content/353/6297/399
It frustrates me no end that journalists writing news articles NEVER provide links to the source material. Grrr.
CDK5 was disrupted in this study by short hairpin (aka small hairpin) RNA interference and by CRISPR (genome editing), neither of which have reached the point of widespread testing in clinical trials.
DeleteInterestingly there has been reason to think about "availability of potent, selective, brain permeable cdk5 inhibitors" as a treatment for Alzheimers.
http://www.ncbi.nlm.nih.gov/pubmed/12540052
Pfizer has an experimental compound called CP-681301 that inhibits CDK5, but I can't see that this has even made it to a phase I safety trial in humans.
Thanks for providing further information on the study.
DeleteIt's interesting that multiple agents being pursued for alzheimer's also have relevance for glioma. In both cases, crossing the blood-brain barrier is a chief obstacle in treatment.
Readers of this blog will recognize several agents in this mouse alzheimer's "cocktail" that many of us use already for glioma:
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014015
"Formulation of a Medical Food Cocktail for Alzheimer's Disease: Beneficial Effects on Cognition and Neuropathology in a Mouse Model of the Disease"
Yes, and Longvida curcumin was specifically designed as an Alzheimer's treatment.
DeleteHello,
Deletesince you just mentioned longvida curcumin...I found article "Curcumin induces glioma stem-like cell formation."
http://www.ncbi.nlm.nih.gov/pubmed/25602852
Any thoughts on that or maybe anyone has access to full article (it isn't free to read)?
Thanks
I'm aware of this study, and do have a copy of it. The study showed essentially two things: 1) inhibition of viability and proliferation of glioma cells at curcumin concentrations between 6.25 and 50 micromolar and 2) induction of stemness markers (CD133, nestin, etc) and stem-like behaviour at a curcumin concentration of 50 micromolar. Given that free concentration of curcumin in plasma is in the neighborhood of 100 nanomolar (500 times less than the concentration used in this study) after a single 2000 mg dose of Longvida, the relevance of this study is far from clear.
DeleteIn vivo studies are always more convincing that most in vitro work, for the simple reason that any concentration of a drug can be used in vitro, while in vivo there are limits, in that the drug cannot be given at such a high concentration that it kills the animal or causes them to lose weight due to treatment toxicity.
My own theory is that curcumin is more likely to be beneficial for glioma due to effects on immune cell populations (especially via inhibition of STAT3), though I don't rule out direct effects. Curcumin can build up to much higher levels in tissues such as brain tissue than it does in plasma, though how much of this is in an unbound, active form is an open question.
Every mouse study I've seen using curcumin showing any effect led to prolonged survival, and this evidence is more trustworthy than the in vitro promotion of stemness at the unachievable (in vivo) concentration of 50 micromolar, in my opinion.
I can upload this study to the Library if anyone desires to read in full.
Yes, please!
ReplyDeleteI uploaded 2 curcumin studies to the Library (folder 2 - preclinical therapies, curcumin subfolder). One is the study where it induced stemness in vitro at 50 micromolar. Another, in direct contrast to the first study, shows curcumin differentiating glioma initiating cells and decreasing their self-renewal at the much more reasonable concentration of 2 micromolar, and also prolonging survival in mice.
DeleteHi Stephen, would it be possible to add a column on achievable serum levels in your non-pharmaceutical list? I'm trying to read as many articles as possible on Pubmed on every suggested supplement to make an opinion on whether or not to include it in the cocktail for my father. But both mode of action (ie what pathways etc it acts on) as well as dosing is very hard for me to interpret as I have no medical background, i.e. is a 100 uM dose at all achievable with supplement X and so on.
DeleteWhat I'm trying to do is compose a large Excel spreadsheet with articles pro and con each supplement and try to make a weighted opinion on whether or not to include it.
Yes, I can add a column to the list. You'll find that 99% of in vitro studies testing nutraceutical type compounds for cancer are using unrealistic concentrations. The matter is complicated by the fact that most pharmacokinetic studies report total plasma concentrations, though it is generally only the free, unbound, fraction that will be pharmacodynamically active. Additionally, metabolites of the ingested substance may also be active (or not) and add to the in vivo effect. I theorize that the mechanisms of action identified by in vitro work is likely often not the operative mechanism of action in vivo, where potential effects on immune cells, tumor vasculature, circulating factors like glucose, insulin, hormones, growth factors, etc, come into play. In vitro systems are extremely simplified compared to living organisms, which probably goes without saying.
DeleteThanks! Yes, I've noticed that most in vitro studies seem to revolve around dosages in the tens or hundreds of micromoles. One problem being that many of the compounds seem to be hormetic with low dosages possibly being tumorpromotive, and thus my thinking goes "what if this supplement actually worsens the situation in the dosages likely to be achievable IRL"?
ReplyDeleteOne study proposed a "nutrient mix" consisting of selenium, EGCG among other substances and found the mix to be tumorpreventive at >500 uM. Looking at the graphs in that study it would however seem that dosages less than that were actually tumorpromotive, unless I misunderstand. (http://www.ncbi.nlm.nih.gov/pubmed/24867464)
Another question that rises is whether some supplements are additive, synergistic or antagonistic with each other?
One study seems to point at TMZ + Curcumin + Resveratrol being highly synergistic when used together (http://www.ncbi.nlm.nih.gov/pubmed/25542083)
In the end I don't know it the supplements make much of a difference or not, but at the moment being that's the only viable option I have since the neurooncologist said strictly no to any off-label prescriptions.