In my June 11 post I mentioned reading about two compounds that effectively eradicate AML at the bulk, progenitor and stem level: celastrol and 4-hydroxy-2-nonenal or HNE (AML stands for acute myelogenous leukaemia, by the way). Well, thanks to Sherlock , I was able to read the whole University of Rochester/University of Pennsylvania study. The abstract can be seen here: http://tinyurl.com/6ltvw5
The full study begins with an acknowledgment of the importance of cancer stem cells, or CSCs, for studies of basic tumor biology and the development of improved therapies. Like normal stem cells, CSCs are thought to reside at the apex of a developmental hierarchy and are responsible for the continued growth and expansion of bulk tumor populations. Consequently, the biological activity of CSCs may contribute to initiation, maintenance, and relapse of at least some forms of cancer. Yes, this sounds all too familiar…
The researchers further comment that several studies have shown that AML stem cells (AML-SCs) are refractory to commonly used clinical agents such as cytarabine and anthracyclines, thereby further supporting the hypothesis that malignant stem cells represent a probable reservoir from which disease relapse may occur. In vitro studies, they continue, have shown that the combination of the chemotherapeutic drug idarubicin and the proteasome inhibitor MG-132 can effectively eradicate leukemia stem cells via a mechanism involving concomitant inhibition of nuclear factor-kB (NF-kB)–mediated survival signals and induction of oxidative stress.
Then they discuss parthenolide (PTL), a substance that can ablate AML-SCs as a single agent. As a single agent, mind you! Impressive. They add that the SC-killing mechanism is similar to the one used by the idarubicin and MG-132 mixture, and that is: combined inhibition of NF-kB and induction of oxidative stress, thus indicating that common biological principles underlie the anti–AML-SC effects of these agents despite their chemical diversity.
The researchers decided to explore other AML stem cell killing possibilities using gene expression signatures. They examined the natural antileukemia characteristics of PTL, which has been shown to induce very potent and specific effects, mediating rapid death of AML-SCs, but not normal hematopoietic stem and progenitor cells, looking for other substances that provoke a similar response in cancer stem cells. They then tested those compounds against AML stem cells.
For this purpose, they used the GEO or Gene Expression Omnibus, a sort of humongous gene expression warehouse. To their surprise, they found a recurring and chemically diverse group of compounds that mimic the PTL gene expression pattern and, like PTL, are capable of ablating AML cells at the bulk, progenitor, and stem-cell level. The sentence that follows is also important: As with PTL, the mechanism of action for these new compounds involves concomitant inhibition of the NF-kB survival signal and induction of oxidative stress, suggesting their general importance in targeting AML stem cells. Sorry to keep repeating “NF-kB plus oxidative stress,” but this is a crucial point, methinks.
The researchers identified and tested four compounds, including the two that I mentioned the other day and that inhibit NF-kB and proteasomes. These two were found to have molecular characteristics comparable to those of PTL. I should note that these compounds, while known for their anticancer activity and for their ability to inhibit NF-kB, had never before been tested for their specific ability to target leukemic stem cells.
By the way, the other two compounds, gedunin and hemin, did not target the AML stem cells and were therefore discarded.
In conclusion, this study is remarkable not only because of the discovery of two new compounds that exterminate AML stem cells, but also because a gene expression database was used to identify potentially useful compounds. Very very interesting approach…