An anti-psychotic drug used to treat schizophrenia appears to get rid of cancer stem cells by helping them differentiate into less threatening cell types. The discovery reported in the Cell Press journal Cell on May 24th comes after researchers screened hundreds of compounds in search of those that would selectively inhibit human cancer stem cells, and it may lead rather swiftly to a clinical trial.
"You have to find something that's truly selective for cancer stem cells," said Mickie Bhatia, lead author of the study from McMaster University. "We've been working for some time and it's hard to find that exact formula."
The survival of cancer patients is largely unchanged from 30 years ago, and many suspect that greater success will come by addressing the rare and chemotherapy-resistant cancer stem cells.
Unlike normal stem cells, cancer stem cells resist differentiating into stable, non-dividing cell types. Bhatia's team exploited this difference to simultaneously screen compounds for their activity against human cancer stem cells versus normal human stem cells.
By testing hundreds of compounds, they identified nearly 20 potential cancer stem cell specific drugs. The one that appeared most promising is an antipsychotic drug, thioridazine, which is known to work against schizophrenia by targeting dopamine receptors in the brain. The drug doesn't appear to kill cancer stem cells, but rather encourages them to differentiate, thus exhausting the pool of self-renewing cells.
The researchers showed that thioridazine kills leukemia stem cells without affecting normal blood stem cells. Comparing the proteins in leukemia versus normal blood cells helped to explain this specificity. The leukemia cells, but not normal blood stem cells, express a dopamine receptor on their surfaces. Dopamine receptors also appear on some breast cancer stem cells, they found.
"This gives us some explanation," Bhatia said. It also suggests that dopamine receptors might serve as a biomarker for rare, tumor-initiating cells.
In light of the findings, Bhatia's team is already planning for a clinical trial of the FDA-approved thioridazine in combination with standard anti-cancer drugs for adult acute myeloid leukemia.
"We're excited about bringing this drug to patients," Bhatia said. "We also hope our platform can now be a pipeline for other cancer stem cells drugs."
- Eleftherios Sachlos, Ruth M. Risueño, Sarah Laronde, Zoya Shapovalova, Jong-Hee Lee, Jennifer Russell, Monika Malig, Jamie D. McNicol, Aline Fiebig-Comyn, Monica Graham, Marilyne Levadoux-Martin, Jung Bok Lee, Andrew O. Giacomelli, John A. Hassell, Daniela Fischer-Russell, Michael R. Trus, Ronan Foley, Brian Leber, Anargyros Xenocostas, Eric D. Brown, Tony J. Collins, Mickie Bhatia. Identification of Drugs Including a Dopamine Receptor Antagonist that Selectively Target Cancer Stem Cells. Cell, 2012; DOI: 10.1016/j.cell.2012.03.049
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