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Biological Chemistry

Platinum-containing cancer drugs have different mechanisms

Unlike cisplatin, oxaliplatin works by inducing ribosome biogenesis stress

by Celia Henry Arnaud
March 6, 2017 | APPEARED IN VOLUME 95, ISSUE 10

Platinum-containing drugs are used to treat many types of cancer. Drugs such as carboplatin and oxaliplatin were developed to avoid some of the side effects and treatment resistance associated with traditional cisplatin. Researchers thought all these drugs kill cells by triggering a DNA-damage response. But oxaliplatin has an unusual side-effect profile and works against cancers for which other drugs, such as cisplatin, are minimally effective. A team led by Michael T. Hemann and Stephen J. Lippard of MIT now demonstrates that oxaliplatin works through a different mechanism (Nat. Med. 2017, DOI: 10.1038/nm.4291). The researchers used RNA interference to target genes with known or suspected roles in cell-death signaling pathways and to see how those pathways responded to various platinum-containing drugs. They found that instead of killing cells through DNA damage, oxaliplatin induces ribosome biogenesis stress, in which cells produce large quantities of the protein-translation machinery, throwing protein production out of whack. In a bit of a vicious cycle, ribosome biogenesis stress may further sensitize cells to oxaliplatin. The findings suggest that platinum drugs don’t necessarily function interchangeably with their derivatives, the researchers note.

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