Targeting Resistance

RESEARCH HIGHLIGHTS

DRUG RESISTANCE Targeting resistance

overcome E6-induced resistance restore doxorubicin lethality. These should restore doxorubicin’s lethality included quaternary ammonium in RKO-E6 cells. Nearly 30,000 com- compounds, protein-synthesis pounds were tested in the primary inhibitors and a class of small screen, and 278 of these were lethal. molecules that included 1,3-bis(4- A secondary screen eliminated those morpholinymethyl)-2-imidazo- compounds that did not depend on lidinethione. The authors named E6 and doxorubicin to induce cell another previously unexplored class death — 88 compounds remained. of small molecules indoxins, for their So, what is the basis of the ability to increase the lethality of resensitization activity of these 88 doxorubicin selectively. All of these compounds? Surprisingly, only classes of compounds upregulated one compound affected the expres- topoisomerase IIα and/or induced sion level of p53, so the authors S-phase arrest in RKO-E6 cells. developed a pathway-based analysis To further elucidate the mecha- using a co-treatment strategy to nism of action of the indoxins, the determine how the compounds authors synthesized a series of functioned. In this analysis, indoxin analogues and used indoxin Most cancer cells acquire resistance compounds that increased the affinity probes to identify their pro- to apoptosis-inducing drugs such as sensitivity of RKO-E6 cells to the tein targets. One of the five proteins the widely used drug doxorubicin. Further microtubule inhibitor podophyl- identified was myosin 1c. In keeping Brent Stockwell and colleagues used lotoxin, the topoisomerase-I-based with its known functions, it is pos- high-throughput cell-viability screen- investigation DNA-damaging agent camp- sible that nuclear myosin 1c mediates ing and a pathway-based analysis to of these tothecin, and doxorubicin were topoisomerase IIα transcription, find compounds that increase the doxorubicin- assumed to act through general cell- whereas myosin 1c in the cytosol lethality of doxorubicin in cancer enhancing death mechanisms and were elimi- might mediate S-phase arrest. cells that are resistant to it. nated. Compounds that increased Further investigation of these Two colon carcinoma cell lines small sensitivity to both camptothecin and doxorubicin-enhancing small were used for the screens. One cell molecules for doxorubicin but not podophyllotoxin molecules for the adjuvant treatment line (RKO) expressed high levels of the adjuvant presumably act downstream of the of doxorubicin-resistant cancer is the DNA-damage-response protein DNA-damage response. Compounds warranted. p53 and was sensitive to doxorubicin treatment of that synergized only with doxorubicin Ezzie Hutchinson

(a topoisomerase-II-based DNA- doxorubicin- were likely to operate at the level of, ORIGINAL RESEARCH PAPER Smukste, I., damaging agent). The other cell resistant or upstream of, topoisomerase II Bhalala, O., Perisco, M. and Stockwell, B. R. Using line (RKO-E6) expressed the viral proteins. These last two groups of small molecules to overcome drug resistance cancer is induced by a viral oncogene. Cancer Cell 9, oncoprotein E6, which induces compounds were studied in more 133–146 (2006) p53 degradation, and was relatively warranted. detail. Brent Stockwell’s lab: http://www.columbia. edu/cu/biology/faculty/stockwell/StockwellLab/ resistant to doxorubicin. The authors The authors found several groups index/index.html reasoned that compounds that of compounds with the potential to

RESEARCH HIGHLIGHTS ADVISORS AVI ASHKENAZI Genentech, Inc., MARIA BLASCO RAKESH JAIN JOHN D. POTTER BERT VOGELSTEIN South San Francisco, CA, USA Spanish National Cancer Centre Massachusetts General Hospital, Fred Hutchinson Cancer The Sidney Kimmel Comprehensive JOSE BASELGA (CNIO), Madrid, Spain Boston, MA, USA Research Center, Seattle, Cancer Center, Baltimore, MD, USA Vall d’Hebron University Hospital, RON DEPINHO Harvard Medical CHRISTOPH LENGAUER WA, USA ROBERT WEINBERG Barcelona, Spain School, Boston, MA, USA Novartis Institute for Biomedical DAVID SIDRANSKY Whitehead Institute for Biomedical ANTON BERNS GLENN DRANOFF Research Inc., Cambridge, MA, USA Johns Hopkins University Research, Cambridge, MA, USA Netherlands Cancer Institute, Dana–Farber Cancer Institute, LANCE LIOTTA National Cancer School of Medicine, Baltimore, ZENA WERB University of California Amsterdam, The Netherlands Boston, MA, USA Institute, Bethesda, MD, USA MD, USA at San Francisco, CA, USA