NEWS OF TH E WEEK
NEW ANTICANCER TARGET IDENTIFIED DRUG DISCOVERY: Cancer cells
need MTH1 enzyme to thrive; inhibiting it kills them
tentially minimal side effects could spark a new round of drug discovery efforts. In two new papers, researchers confirm earlier hints that an enzyme called MTH1 is critical for cancer cell proliferation. They identified inhibitors of the enzyme and showed that the compounds suppress tumor growth in cancerous mice. In addition, they found that an anticancer agent of previously unknown mechanism works by inhibiting MTH1 and also identified another inhibitor with better drug properties. Cancer cells produce new cells rapidly and thus require a constant supply of new DNA. But because cancer cells are interlopers that develop under stressful conditions in the body, bases produced in cancer cells for DNA replication tend to be damaged oxidatively much more frequently than those found in normal cells. Cancer cells can withstand such damage because MTH1 protects them: The enzyme blocks these damaged bases from being incorporated into replicating DNA. It does the job so well that cancer cells thrive. Thomas Helleday of the Karolinska Institute, in Stockholm, and coworkers have now validated MTH1 as an anticancer target and have treated cancer cells with TH287 and TH588, two MTH1 inhibitors they developed (Nature 2014, DOI: 10.1038/nature13181). The inhibitors block MTH1’s activity, allowing oxidatively damaged bases in the cancer cells to make their way into replicating DNA. The resulting DNA damage sup-
ADAPTED FROM NATURE
A
NOVEL STRATEGY for fighting cancer with po-
presses growth of human skin, colorectal, and breast tumors grafted into mice. And Giulio Superti-Furga of CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, and coReplication produces workers found that SCH51344, an anticancer normal DNA agent discovered earlier, works by targeting MTH1. They also identified another MTH1 MTH1 inhibitor with better drug properCancer cell ties—(S)-Crizotinib, the enantiomer of with oxidatively an approved Pfizer non-small-cell lung damaged cancer drug (Nature 2014, DOI: 10.1038/ bases nature13194). (S)-crizotinib stifles tumor MTH1 inhibition growth in a mouse model of colon cancer. “The Helleday and Superti-Furga labs have done a stellar job of showing how MTH1 inhibition can effectively target a number of tumor cell lines,” comments MTH1 expert Priyamvada Rai of the University Replication of Miami School of Medicine. She notes that produces a German group also recently identified damaged a potent MTH1-specific inhibitor (AnDNA, leading to cell death gew. Chem. Int. Ed. 2014, DOI: 10.1002/ anie.201307849). The studies represent “an exciting new apSANITIZER MTH1 blocks proach” for targeting differences between tuoxidatively damaged bases mor and normal cells, says Margherita Bignami from the DNA replication of the National Institute of Health, in Rome, a process in cancer cells. specialist on oxidative stress in cancer. But she Inhibiting it leads to genetic cautions that MTH1 also prevents mutations damage and cancer cell and senescence in normal cells and protects the death. brain, so inhibiting it could turn out to cause side effects. Helleday acknowledges that further work is needed and that any clinical trials of MTH1 inhibitors are at least one to two years away.—STU BORMAN VIDEO ONLINE
To see how inhibiting MTH1 kills cancer cells, go to http://cenm.ag/mth1.
CHINA Another round of protests erupts against polyester intermediate p-xylene Protests against plans to build a p-xylene plant turned violent last week in the southern China city of Maoming. The protests were the latest by the Chinese public against a chemical that has come to symbolize the risks associated with chemical production. Police arrested 19 demonstrators on March 30 who were part of a small and initially peaceful demonstration that attracted 80 people, according to a Maoming government statement. Amateur videos posted on YouTube indicate that far more than 80 people were involved. Authorities claim the event turned
violent when protesters started throwing water bottles and stones at police. The government said no one died but did not specify how many people were injured. Authorities later stated that the p-xylene project has yet to be approved and will not go ahead without public consensus. It would be part of an expansion at a subsidiary of the state-owned oil giant Sinopec. Derived from oil refinery side streams, p-xylene is used to manufacture polyester fiber and plastics. The substance is toxic but less so than other chemicals commonly made in China such as benzene or vinyl chloride.
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Chinese protests against p-xylene began in 2007 in Xiamen when citizens forced the relocation of a construction project. Global Times, a state-controlled publication known for its nationalist tone, published an editorial last week stating that turning to imports of p-xylene, known as PX, would pose a “strategic risk” for China. “A lack of communication between local governments and the public, plus poor official credibility, constitute the roots of local repugnance against PX projects,” the editorial said.—JEANFRANÇOIS TREMBLAY
