{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:49:35Z","timestamp":1791474575174,"version":"4.3.4"},"reference-count":36,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2011,7,27]],"date-time":"2011-07-27T00:00:00Z","timestamp":1311724800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>HSP90 plays a central role in stabilizing client proteins involved in malignant processes. SNX\u20102112 is an orally administered potent HSP90 inhibitor that has demonstrated pre\u2010clinical anti\u2010tumor activity in adult malignancies. As many childhood tumors depend upon HSP90 client proteins, we sought to test the pre\u2010clinical efficacy of SNX\u20102112 in a panel of pediatric cancer cell lines both as a single\u2010agent and in combination with cisplatin (CP).<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p>Eight cell lines (from osteosarcoma, neuroblastoma, hepatoblastoma, and lymphoma) were studied. Short\u2010 and long\u2010term effects of SNX\u20102112 were assessed by MTT and clonogenic assays. Cell cycling was measured using flow cytometry. Status of HSC70, HSP72, AKT1, C\u2010Raf, and PARP was assessed by immunoblotting. Efficacy of SNX\u20102112 in combination with CP was assessed using median\u2010effect analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cell lines studied demonstrated sensitivity to SNX\u20102112 with IC<jats:sub>50<\/jats:sub> values ranging from 10\u2013100\u2009nM. Low dose treatments (12\u2009nM) resulted in a cytostatic response with a minimal increase in sub\u2010G1 content. A higher dose (70\u2009nM) exhibited a more prolonged inhibition and larger sub\u2010G1 accumulation. Observed levels of AKT1 and C\u2010Raf were markedly reduced over time along with an increase in PARP cleavage. In concurrently administered combination treatments, SNX\u20102112 and CP synergistically inhibited cell growth.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>SNX\u20102112 showed marked single\u2010agent activity in pediatric cancer cell lines with downstream effects on HSP90 client proteins. The combination of SNX\u20102112 and CP showed synergistic activity in two cell lines tested. Further studies of HSP90 inhibitors such as SNX\u20102112 as a single agent or in combination with chemotherapy are warranted in pediatric cancer. Pediatr Blood Cancer 2012; 58: 885\u2013890. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.23270","type":"journal-article","created":{"date-parts":[[2011,7,27]],"date-time":"2011-07-27T22:51:31Z","timestamp":1311807091000},"page":"885-890","source":"Crossref","is-referenced-by-count":16,"title":["Anti\u2010tumor activity of the HSP90 inhibitor SNX\u20102112 in pediatric cancer cell lines"],"prefix":"10.1002","volume":"58","author":[{"given":"Danielle C.","family":"Chinn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William S.","family":"Holland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet M.","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore","family":"Zwerdling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip C.","family":"Mack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,7,27]]},"reference":[{"key":"e_1_2_6_2_2","volume-title":"Cancer Facts and Figures 2010","author":"Society AC","year":"2010"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2010.02.007"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.20611"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1677\/erc.1.01324"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R800007200"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.12.024"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2887"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-0132"},{"key":"e_1_2_6_10_2","article-title":"Targeting heat shock proteins in cancer","author":"Jego G","year":"2010","journal-title":"Cancer Lett"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.2174\/156802609789895728"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568009033481859"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/3-540-29717-0_14"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-2270"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-1667"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-04-151928"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2009.04.046"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.337"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0065-2571(84)90007-4"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0609973103"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.20.13047"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M000434200"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.08.002"},{"key":"e_1_2_6_24_2","first-page":"1721","article-title":"Benzoquinonoid ansamycins possess selective tumoricidal activity unrelated to src kinase inhibition","volume":"52","author":"Whitesell L","year":"1992","journal-title":"Cancer Res"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1080\/713803536"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24660"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0683"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-0253"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1097\/CAD.0b013e3282ef532d"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb05605.x"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206794"},{"key":"e_1_2_6_32_2","first-page":"8233","article-title":"Chemosensitization by a non\u2010apoptogenic heat shock protein 70\u2010binding apoptosis\u2010inducing factor mutant","volume":"63","author":"Schmitt E","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-007-0662-x"},{"key":"e_1_2_6_34_2","first-page":"2228","article-title":"Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy\u2010induced apoptosis in an RB\u2010 and schedule\u2010dependent manner. 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