Researchers from the Technical University of Munich (TUM) claim to have discovered the molecular mechanism for the sedative thalidomide (Thalomid, Celgene). The findings could help to improve cancer treatment Nat Med. 2016 Jun 13.
Thalidomide, an immunomodulatory drug developed in West Germany during the 1950s, was marketed in Europe as the first safe sleeping pill—even for pregnant women. It was later linked to birth defects (e.g., flipperlike arms and legs) in children whose mothers took the drug during pregnancy.
Thalidomide was banned worldwide in 1962, and re-emerged into the medical scene in the 1990s when it showed potential for treating cancer and other medical conditions.
The TUM researchers found that the mechanism that causes birth defects is the same that gives the drug its anticancer properties: The drug prevents the proteins CD147 and MCT1 from binding to cereblon, a cellular protein.
“The mechanisms are identical,” said Florian Bassermann, MD, study author, in a press release. “A specific inactivation of the protein complex resulted in the same developmental defects observed in the thalidomide treatment.”
This protein complex is usually found in blood-building and immune cells, and promotes the formation of new blood vessels; it also allows tumor cells to multiply and spread rapidly in some forms of cancer, according to the researchers. The drug disrupts the complex from joining and activating, leading to improper development of blood vessels. This in turn “causes the tumor cells to die,” Ruth Eichner, MD, first study author, said in the press release.
The CD147 and MCT1 proteins also vanished in patients who responded well to immunomodulatory drug treatment, the researchers reported. They suggested that this could help to assess which patients would most likely benefit from receiving these medications by testing cultures of a patient’s tumor cells for disruption. The findings also highlight the need for more research to find other methods—with less potential side effects—to deactivate this protein complex.
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