w 14 | ive from the Labs cnrsI InternatIonal magazIne L Biology Tworecently-publishedresults,oneexploitingtheHIVmachinery,the otherinvolvinganewcytoskeletoninhibitor,couldleadtobettercancertreatments. Fighting Cancer on All Fronts Dynamic microtubules 02 BY clémentInewallace Control uone of humanity’s greatest villains. And this is exactly therapy. The LIM kinase (LIMK) enzyme,-The second study concerns analternative anti-cancer treatment forcells resistant to conventional chemowould provide a sense of victory oversing the human immunodeficiency virus (HIV) to curecancer patients what a team of CNRS researchers have in mind. “HIV is which is overexpressed in cancer cells, capable of producing a number of molecules that don’t had already been identified as a exist naturally, much like a mutant factory,” explains team potential new therapeutic target. LIMK leader Matteo Negroni, from the IBMC.1 “So we tried to use plays a central role in regulating the this to our advantage.” dynamics of the cytoskeleton microtu- Pyr1bules and actin filaments and the cell’sThe IBMC team knew that researchers had long been trying to develop a more potent version of a human enzyme called overall motility. However, very few deoxycytidine kinase (dCK), key to the effectiveness of antican- selective LIMK inhibitors have been cer drugs once they enter the organism. “If dCK can be improved explored to date. to better phosphorylate anti-cancer drugs, their effectiveness Now, a collaboration of researchers could be enhanced,” he explains. from France, Australia, and the UK say Going a step further, they investi- In their experiments,2 the researchers inserted a copy of the they have discovered the long-sought gated whether their selection contained dCK gene into the HIV genome, and let it replicate in a culture agent.3 They used an automated high- an agent capable of specifically of human cells. The team then collected the produced mutants, throughput screening tool to analyze inhibiting LIMK. “With the help of luck, and tested them along with anticancer drugs in a culture of more than 30,000 molecules, selecting it did,” as principal investigator human tumor cells. By doing so, they eventually identified a those capable of acting on microtubules, Laurence Lafanechère4 puts it. The team variant capable of boosting the efficiency of anti-cancer drugs a phenomenon that can be visualized by called this agent Pyr-1.In vitro analysis 60-fold, as compared to the wild-type dCK. using specific markers. then revealed that Pyr-1 was toxic to several cancerous epithelial cell lines, including ones that are resistant to drug kills cancer cells OSSOLILLO current therapies.“By blocking LIMK, Pyr-1 targets anemcitabineghet 01 more efficiently in the presence of the P. enzyme involved in several physiologicalR mutant dck (red) EGRONIET pathways: it blocks cell multiplication as compared to and motility. Pyr-1 is not only a new anti- wt dck (blue) or © tumor agent, it’s also potentially anti-M. no dck at all (green). metastatic,” says Lafanechère, outlining that 90% of cancer deaths are generally caused by metastases. 01.Institutdebiologiemoléculaireetcellulaire(CNRS) (TeamArchitectureetréactivitédel’ARN). 02. Rossolilloetal.,“Retrovolution:HIV-driven EvolutionofCellularGenesandImprovement ofAnticancerdrugActivation,”PLoS Genetics, Strasbourg 2012.8:e1002904. 03. Prudentetal.,“PharmacologicalinhibitionofLIM Kinasestabilizesmicrotubulesandinhibits 10 µm neoplasticgrowth,”Cancer Res.,2012.72:4429-39. Grenoble 04.InstitutAlbertBonniot(CNRS/Inserm/université JosephFourier)(Team3Polarity,developmentand Cancer).
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