Chemical News Pharmaceuticals
Antipsychotic drug targets cancer stem cells Thioridazine, a drug normally prescribed as an antipsychotic, has been found by researchers at McMaster University to also target cancer stem cells. The finding led to the identification of new biomarkers that could lead to early cancer detection. Cancer stem cells are hard to identify because they look so much like normal stem cell counterparts. Their distinguishing characteristic is their ability to regenerate without differentiating into other tissues, which keeps tumours coming back even after radiationor chemotherapy. Mickie Bhatia of McMaster’s Department of Biochemistry and Biomedical Sciences and his colleagues developed a high-throughput screen to compare the effect of a given drug on both pluripotent stem cells and cancer stem cells. “Previous screens looked at the ability of drugs to kill cancer stem cells,” Bhatia explains. “We were simply trying to make them differentiate like normal stem cells, something others hadn't done.” In a paper recently published in Cell, they tested 2,600 off-patent drugs of which only about one per cent showed activity. Thioridazine had one of the strongest and most selective effects,
causing differentiation of cancer stem cells but leaving normal ones alone. Since differentiated cells eventually die, thioridazine could serve as an effective therapeutic against cancers like leukemia. Thioridazine is known to inhibit dopamine receptors. Further investigation showed that these receptors are indeed present in greater concentrations on the surface of cancer stem cells, indicating a potential new biomarker of cancer. “What’s so exciting about this work is the ability to use these chemicals beyond just drug response, as a way of probing signalling pathways that might be relevant to distinguishing cancer stem cells from normal ones,” says Bhatia.
The antipsychotic drug thioridazine, one enantiomer of which is shown here, can selectively target cancer stem cells and cause them to differentiate.
materials
Wheels on the MOF go round and round
To ‘spin one’s wheels’ usually means a failure to make progress, but last month a group of researchers from the University of Windsor spun themselves onto the cover of Nature Chemistry. They’ve created the first metal-organic framework (MOF) with rotating dynamic components; the innovation could bring us one step closer to molecular computing. Stephen Loeb’s group in Windsor’s Department of Chemistry specializes in rotaxanes, a type of mechanically interlocked molecule where a cyclical ‘wheel’ freely rotates around a straight ‘axle.’ Large functional groups on either end of the axle prevent the wheel from slipping off. The group has even created rotaxanes where a single wheel can jump between two discrete locations on an axle, acting as a molecular switch that could encode digital information. Until now such molecules had only been made in solution. “If you want to make random access memory using these things, then you’ve got to organize them in some way,” says Loeb. In the paper, the group describes a simple rotaxane in which the functional groups on the end have been modified into carboxylate groups. These groups interact with copper-based metal-organic complexes to form a solid-state, three-dimensional MOF. Experiments using NMR with deuterium labelling conducted by Robert Shurko’s group
12 CAnadian Chemical News
july | AUGUST 2012