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Gene expression analysis of B‐lymphoma cells resistant and sensitive to bortezomib *
Author(s) -
Shringarpure Reshma,
Catley Laurence,
Bhole Deepak,
Burger Renate,
Podar Klaus,
Tai YuTzu,
Kessler Benedikt,
Galardy Paul,
Ploegh Hidde,
Tassone Pierfrancesco,
Hideshima Teru,
Mitsiades Constantine,
Munshi Nikhil C.,
Chauhan Dharminder,
Anderson Kenneth C.
Publication year - 2006
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2006.06132.x
Subject(s) - bortezomib , proteasome inhibitor , cancer research , proteasome , multiple myeloma , mantle cell lymphoma , apoptosis , lymphoma , chemistry , pharmacology , immunology , biology , biochemistry
Summary The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM). Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. However, resistance to bortezomib as a single agent develops in the majority of patients, and activity in other malignancies has been less impressive. To elucidate mechanisms of bortezomib resistance, we compared differential gene expression profiles of bortezomib‐resistant SUDHL‐4 and bortezomib‐sensitive SUDHL‐6 diffuse large B‐cell lymphoma lines in response to bortezomib. At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in SUDHL‐6 cells, but not in SUDHL‐4 cells. We showed that overexpression of activating transcription factor 3 (ATF3), ATF4, ATF5, c‐Jun, JunD and caspase‐3 is associated with sensitivity to bortezomib‐induced apoptosis, whereas overexpression of heat shock protein (HSP)27, HSP70, HSP90 and T‐cell factor 4 is associated with bortezomib resistance.