{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T20:48:44Z","timestamp":1778100524455,"version":"3.51.4"},"reference-count":62,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,1,30]],"date-time":"2013-01-30T00:00:00Z","timestamp":1359504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2013,4]]},"abstract":"Summary<\/jats:title>Interactions between the Bruton tyrosine kinase (BTK<\/jats:styled-content>) inhibitor PCI<\/jats:styled-content>\u201032765 and the proteasome inhibitor (bortezomib) were examined in diffuse large\u2010B cell lymphoma (DLBCL<\/jats:styled-content>) and mantle cell lymphoma (MCL<\/jats:styled-content>) cells, including those highly resistant to bortezomib. Co\u2010administration of PCI<\/jats:styled-content>\u201032765\/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre\u2010 or activated B\u2010cell\u2010like\u2010DLBCL<\/jats:styled-content> cells and in MCL<\/jats:styled-content> cells. These events were accompanied by marked AKT<\/jats:styled-content> and nuclear factor (NF<\/jats:styled-content>)\u2010\u03baB (NFKB<\/jats:styled-content>1) inactivation, down\u2010regulation of Mcl\u20101 (MCL1), Bcl\u2010xL<\/jats:styled-content> (BCL<\/jats:styled-content>2L1), and XIAP<\/jats:styled-content>, and enhanced DNA<\/jats:styled-content> damage (e.g., \u03b3H2A.X formation) and endoplasmic reticulum (ER<\/jats:styled-content>) stress. Similar interactions were observed in highly bortezomib\u2010resistant DLBCL<\/jats:styled-content> and MCL<\/jats:styled-content> cells, and in primary DLBCL<\/jats:styled-content> cells. In contrast, PCI<\/jats:styled-content>\u201032765\/bortezomib regimens displayed minimal toxicity toward normal CD<\/jats:styled-content>34+<\/jats:sup> bone marrow cells. Transfection of DLBCL<\/jats:styled-content> cells with a constitutively active AKT<\/jats:styled-content> construct attenuated AKT<\/jats:styled-content> inactivation and significantly diminished cell death, whereas expression of an NF<\/jats:styled-content>\u2010\u03baB \u201csuper\u2010repressor\u201d (I\u03baB\u03b1ser34\/36<\/jats:sub>) increased both PCI<\/jats:styled-content>\u201032765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant\u2010negative eIF<\/jats:styled-content>2\u03b1 construct were resistant to this regimen. Finally, combined exposure to PCI<\/jats:styled-content>\u201032765 and bortezomib resulted in more pronounced and sustained reactive oxygen species (ROS<\/jats:styled-content>) generation, and ROS<\/jats:styled-content> scavengers significantly diminished lethality. Given promising early clinical results for PCI\u201032765 in DLBCL<\/jats:styled-content> and MCL<\/jats:styled-content>, a strategy combining BTK<\/jats:styled-content>\/proteasome inhibitor warrants attention in these malignancies.<\/jats:p>","DOI":"10.1111\/bjh.12206","type":"journal-article","created":{"date-parts":[[2013,1,30]],"date-time":"2013-01-30T06:59:21Z","timestamp":1359529161000},"page":"43-56","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["The Bruton tyrosine kinase (BTK<\/scp>) inhibitor PCI<\/scp>\u201032765 synergistically increases proteasome inhibitor activity in diffuse large\u2010B cell lymphoma (DLBCL<\/scp>) and mantle cell lymphoma (MCL<\/scp>) cells sensitive or resistant to bortezomib"],"prefix":"10.1111","volume":"161","author":[{"given":"Girija","family":"Dasmahapatra","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology Department of Medicine Virginia Commonwealth University Richmond VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiral","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology Department of Medicine Virginia Commonwealth University Richmond VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Dent","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Virginia Commonwealth University Richmond VA USA"},{"name":"Department of Biochemistry Virginia Commonwealth University Richmond VA USA"},{"name":"Department of Molecular and Human Genetics Virginia Commonwealth University Richmond VA USA"},{"name":"Massey Cancer Center Virginia Commonwealth University Richmond VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard I.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Division of Hematology Oncology University of Rochester Medical Center and the James P. Wilmot Cancer Center Rochester NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Friedberg","sequence":"additional","affiliation":[{"name":"Division of Hematology Oncology University of Rochester Medical Center and the James P. Wilmot Cancer Center Rochester NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Grant","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology Department of Medicine Virginia Commonwealth University Richmond VA USA"},{"name":"Department of Biochemistry Virginia Commonwealth University Richmond VA USA"},{"name":"Department of Molecular and Human Genetics Virginia Commonwealth University Richmond VA USA"},{"name":"Massey Cancer Center Virginia Commonwealth University Richmond VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,1,30]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"2615","article-title":"Proteasome inhibitors: a novel class of potent and effective antitumor agents","volume":"59","author":"Adams J.","year":"1999","journal-title":"Cancer Research"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400436"},{"key":"e_1_2_9_4_1","first-page":"4969","article-title":"The Bruton's Tyrosine Kinase (BTK) Inhibitor PCI\u201032765 Inhibits Growth of ABC DLBCL Tumors In Vivo and in Vitro by Preventing Activation of Pro\u2010Survival NF\u2010{kappa}B pathways","volume":"117","author":"Balbasubramanian S.","year":"2011","journal-title":"Blood (ASH annual Meeting Abstracts)"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-04-1399"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3321"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.2012.640318"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1069398"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-0257"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0065-2571(84)90007-4"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07968"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.43.30644"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206863"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.13.5429-5444.2005"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.8.9.8131"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-12-257261"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-10-1108"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0021"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80405-5"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.22.2905"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08638"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-01-199679"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.07.9665"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208530"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.03.108"},{"key":"e_1_2_9_26_1","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nrd3656","article-title":"Trial watch: BTK inhibitor shows positive results in B cell malignancies","volume":"11","author":"Harrison C.","year":"2012","journal-title":"Nature reviews. 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