Selenite against mesothelioma – mechanism of action explained

ResearchBlogging.org

Our latest paper is now freely available online as a fully formatted pdf from the Journal of Experimental and Clinical Cancer Research. As I have promised, here is a non-technical summary!

What did we study?

This work is about malignant mesothelioma, an unusual type of cancer that is caused by asbestos. It is always deadly, and current treatment extends life expectancy only by a few months. We have been working for some time on a new experimental drug called selenite – a simple, selenium-based compound.

Interestingly, mesothelioma cells come in two kinds – epithelioid and sarcomatoid. If a tumor contains sarcomatoid cells, the patient will be expected to respond worse to therapy and die sooner. We have previously found that selenite is particularly effective against sarcomatoid cells, and that it is able to induce apoptosis, the “suicide program” of the cancer cells.

In this paper, we studied the apoptosis mechanisms in both epithelioid and sarcomatoid cells, to see if there were any differences that could explain why sarcomatoid cells are more sensitive. Also, very little was known about the apoptotic response to selenite in mesothelioma cells, we wanted to see how they compare to other cells.

What did we find?

Selenite caused the activation of a number of apoptosis signaling molecules. There was a difference between sarcomatoid and epithelioid cells in the activation of two proteins in the so-called Bcl-family. Sarcomatoid cells clearly overexpressed a protein called Bax. Perhaps this is part of the reason why they are more sensitive to selenite.

There is a “master regulator” of apoptosis called p53, and we investigated it rather thoroughly. It turned out that the cells amassed lots of p53 in their nuclei after selenite treatment, but it didn’t do anything! Normally, it would regulate the DNA and determine which genes should be read. But after selenite treatment, p53 became inactive and unable to regulate gene expression.

Cells stained for p53. Brown nuclei contain much p53 that is inactive. A and C are controls, B and D are treated with selenite. Sell the full paper for details (figure 2).

Cells stained for p53. Brown nuclei contain much p53 that is inactive. A and C are controls, B and D are treated with selenite. Sell the full paper for details (figure 2).

My greatest surprise was that the apoptosis signaling network was so robust and redundant. It’s really not a well-defined linear cascade of events, but rather an interlaced network of protein interactions which depend on and modulate each other. In this paper, we found that inhibition of some of the major apoptosis-signalling proteins had virtually no effect at all on the events following selenite treatment, even though we could prove that the inhibitors were effective in themselves.

What are the implications for the future?

We hope that selenite will become a useful drug for the treatment of mesothelioma in the future. If so, part of its mechanism of action has now been established.

Check out the full paper, it’s open access!

Nilsonne, G., Olm, E., Szulkin, A., Mundt, F., Stein, A., Kocic, B., Rundlöf, A., Fernandes, A., Björnstedt, M., & Dobra, K. (2009). Phenotype-dependent apoptosis signalling in mesothelioma cells after selenite exposure Journal of Experimental & Clinical Cancer Research, 28 (1) DOI: 10.1186/1756-9966-28-92

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5 Responses to Selenite against mesothelioma – mechanism of action explained

  1. [...] the original post: Selenite against mesothelioma – mechanism of action explained Share and [...]

  2. M.o.M. says:

    Impressive!

  3. AK says:

    AFAIK the vast majority of biological networks are robust and redundant. The evolutionary logic behind this seems rather subtle to me, and I’m not sure I understand it (yet) well enough to write a post about it, but a book I recommend is Robustness and Evolvability in Living Systems by Andreas Wagner.

    In a general sense, in terms of the old population genetics, if a mutation in one path causes it to fail, another path can take up the load; this means that as long as low levels of each mutation are present in the population there will be an evolutionary incentive to maintain the robust redundancy.

  4. evolvingideas says:

    Yes, I agree that most biological networks seem to be robust and redundant.

    Thanks for the book tip! I’ve actually read Wagner’s book since I started to take an interest in this question. He argues (among other things) that when several redundant mechanisms encode information, perform calculations, and execute behaviour, the system has a far greater potential to be evolutionarily dynamic, since there are many points at which a certain pathway could establish a connection with another pathway. If I understand him correctly, that is.

  5. Charles says:

    I agree with your post ! nice info about biological networks.

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