Dyclonine, The Active Ingredient In Sucrets, May Enhance The Anti-Myeloma Activity Of Velcade
Results of a small preclinical study conducted at the Karmanos Cancer Center in Detroit indicate that the oral anesthetic dyclonine may enhance the anti-myeloma activity of Velcade.
Dyclonine is the active ingredient in the Sucrets brand of sore throat lozenges, which are sold over-the-counter in drugstores and other retailers in Canada and the United States. Sucrets lozenges are marketed by Insight Pharmaceuticals.
The Karmanos researchers conducted laboratory tests of dyclonine's activity against the so-called "RPMI8226" line of myeloma cells, which is commonly used in pre-clinical testing of potential myeloma therapies. The study involved two variants of the RPMI8226 cell line: the standard variant, and a Velcade (bortezomib)-resistant variant.
The researchers exposed samples of the RPMI8226 myeloma cells to solutions that had different concentrations of dyclonine alone, Velcade alone, and dyclonine and Velcade combined.
They found that dyclonine alone had limited anti-myeloma activity. However, when dyclonine was combined with Velcade, the combination was much more effective at killing RPMI8226 myeloma cells than Velcade alone. The addition of dyclonine, the authors write in their paper, "substantially enhanced the cytotoxic effects of bortezomib [Velcade]."
In addition, the combination of dyclonine and Velcade also was effective at killing many of the Velcade-resistant strain of RPMI8226 myeloma cells. This occurred, however, only in instances when the concentration of Velcade in the two-drug combination was considerably higher than was necessary to kill RPMI8226 cells not resistant to Velcade.
Thus, while dyclonine may theoretically make it possible for Velcade to treat myeloma cells that are otherwise resistant to Velcade, the dose of Velcade required to overcome the resistance may be too high to be practical given the side effects patients would likely experience.
The authors of the study decided to investigate the potential anti-myeloma activity of dyclonine combined with Velcade based on the results of an earlier study they had carried out.
In that study, the researchers combined dyclonine with MG132, an experimental breast cancer drug from the same general class of drugs – proteasome inhibitors – that includes Velcade as well as the newer anti-myeloma therapy Kyprolis (carfilzomib). Adding dyclonine to MG132 in the laboratory tests enhanced MG132's effectiveness at killing breast cancer cells.
The results of the previous study, combined with those from the current study, indicate that dyclonine may generally enhance the anti-cancer activity of proteasome inhibitors such as Velcade and Kyprolis.
Although the results of the current study are certainly intriguing, they should be viewed as very preliminary. The study was carried out entirely in the laboratory and entirely in a test tube-like environment. There was no testing of the dyclonine-Velcade combination against myeloma cells in laboratory animals, let alone in patients with multiple myeloma.
In addition, the study tested the activity of the dyclonine-Velcade combination against just a single myeloma cell line. Many pre-clinical studies of potential myeloma therapies test the therapies against several myeloma cell lines, in both test tube environments and in laboratory animals.
It is also the case, unfortunately, that many potential myeloma therapies show early promise in such pre-clinical testing, but then fail to show significant activity when tested in multiple myeloma patients.
Despite these limitations, the Karmanos study raises the interesting possibility that a commonly available over-the-counter drug could enhance the effectiveness of an existing, frequently used myeloma therapy.
For more information, please refer to the study by Ju, D. and Xie, Y., “Dyclonine enhances the cytotoxic effect of proteasome inhibitor bortezomib in multiple myeloma cells,” in Molecular Medicines Report, August, 28, 2014 (online) (abstract).
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Very interesting. Unfortunately, the link to the article abstract is not working for me (my browser says there are too many redirects). I was hoping to answer this question by reading the abstract, so instead I'll ask it here. Why were the researchers looking at dyclonine? What prior work led them down this path? I never would have guessed that Sucrets would have anything to do with fighting cancer, but then I'm not a biologist!
Not sure if I can get this right, but I'll try. Based on work done in yeast, they had reason to believe that inhibiting certain genes would enhance the effect of the proteosome inhibitor MG132 on breast cancer cells. Other work had shown that dyclonine (and a couple of other compounds) would produce this inhibition. Their tests showed that this indeed was the case, and that these compounds worked with MG132 to significantly enhance its effects on breast cancer cells. They then went on to extend this work to myeloma cells treated with bortezomib.
Thanks for your question, Mike B. Mike F's reply is on the mark.
Apparently, many cellular processes in yeast are similar to those in humans. That includes the processes affected by proteasome inhibitors. In addition, the genome of yeast has been extensively documented, and an analysis of the yeast genome suggested that dyclonine could enhance the activity of proteasome inhibitors.
That is what prompted the authors of the current study to carry out their first study looking at the anti-breast cancer activity of dyclonine combined with the proteasome inhibitor MG132.
The full text of the article about the breast cancer study is available at this link:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906854/
Also, the full text of one of the earlier studies that helped identify dyclonine as a drug that might be worth studying further is available here:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC321760/
I did a quick Internet search and, as near as I can tell, dyclonine's primary and only use is as an oral anesthetic and the primary active ingredient in the Sucrets drops. If this were to proceed to animal or human trials, I would think dyclonine would need to be administered intravenously, by injection, or maybe as a pill. I am doubtful that trying to using Sucrets cough drops while on Velcade is going to put enough dyclonine into the blood stream to make any difference.
I did not see anything were dyclonine is even available for any purpose intravenously, by injection, or as a pill, only as the active ingredient in some over-the-counter throat lozenges. So, although dyclonine has been around for many decades, if it were proven to be useful in boosting protease inhibitors for cancer treatments, that would be a new use for the drug and I believe patentable. Whoever develops it would be able to charge a great deal of money for it. I am not seeing how this could become a low cost drug to enhance the effectiveness of Velcade.
Is my thinking wrong about this?
Nonetheless, this is still very good news and the trials to pursue this further will be expensive to conduct, so maybe good profit margins will be needed to encourage a pharmaceutical company to pursue this.
Thanks for your comment, Eric.
We believe you are correct that no intravenous or injectable form of dyclonine has ever been approved by the FDA. Thus, as you suggest, a company might be able to develop such a form of dyclonine and have a certain period of time when it would have exclusive rights to sell the new formulation in the U.S.
We're not lawyers, however, so we can't say for certain that the new formulation would be patentable (we have our doubts, to be honest). But there also are FDA rules that give a company that develops a new formulation of an existing drug a certain period of market exclusivity. This protection is not as extensive as patent protection, but it does create some incentives to invest in developing new drug formulations.
Of course, there's another issue to consider. Dyclonine is an anesthetic. What sort of effect will high, intravenously administered doses of the drug have on patients? This will need to be investigated in clinical trials if the doses of dyclonine that make a difference in myeloma therapy are considerably higher than what is achieved through everyday use of the OTC formulation of the drug.
And, of course, all of this assumes that further pre-clinical testing of dyclonine provides additional evidence that it enhances the anti-myeloma activity of Velcade and/or other proteasome inhibitors.
How did dyclonine being an anesthetic get past me? Great point, I wonder how that would feel having it injected or administered through IV. Would you go completely numb around the injection site? Imagine walking out of the infusion center with your whole arm or side completely numb.
I would think the researchers would consider that before experimenting with it as a myeloma treatment. But maybe they are simply trying to confirm their theory from previous studies of the yeast genome that dyclonine may enhance proteasome inhibitor effectiveness, and it is nothing more than that, and dyclonine may never be able to be used because of the anesthetic properties. Hopefully not.
Even if dyclonine could never be used, maybe the understanding of how it works will lead to the development of a similar agent that can be used. It would be a great breakthrough in myeloma treatment if they can find ways to make Velcade and Revlimid effective indefinitely.
Hi Eric,
Thanks for the additional comments.
We're not assuming that just because dyclonine is an anesthetic that it could not be further developed for use in anti-myeloma therapy. Given its current use as a throat lozenge, a lot of the drug not only coats the mouth and throat, but probably also enters the bloodstream. So there doesn't seem to be a basic problem with dyclonine floating around through out the body, as opposed to just the mouth and throat.
(Drugs administered in formulations designed to melt in the mouth enter the bloodstream very quickly. It's a key reason some drugs – such as some migraine and pain medications – are administered that way.)
The question therefore seems to be whether, at higher doses, the anesthetic aspect of dyclonine would start to be a problem.
Hopefully, there will be more research done to shed light on that issue, and the current study won't just be a stepping stone to identifying other agents that might improve the efficacy of Velcade and other proteasome inhibitors.
Thanks for the additional information and discussion. It will be interesting to see what happens as a result of these dyclonine studies. I'm glad I asked the question!
Well, I won't hold my breath. How often do we see possible breakthrough therapies and studies come up, only to drop into some black hole, never to be heard of again?
Sorry if that is a downer, but I have been reading this stuff for seven years, and don't see much of it put to practical use.
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