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The Bruton tyrosine kinase ( BTK ) inhibitor PCI ‐32765 synergistically increases proteasome inhibitor activity in diffuse large‐B cell lymphoma ( DLBCL ) and mantle cell lymphoma ( MCL ) cells sensitive or resistant to bortezomib

2013; Wiley; Volume: 161; Issue: 1 Linguagem: Inglês

10.1111/bjh.12206

1365-2141

Girija Dasmahapatra, Hiral Patel, Paul Dent, Richard I. Fisher, Jonathan W. Friedberg, Steven Grant,

CNS Lymphoma Diagnosis and Treatment

Summary Interactions between the Bruton tyrosine kinase ( BTK ) inhibitor PCI ‐32765 and the proteasome inhibitor (bortezomib) were examined in diffuse large‐B cell lymphoma ( DLBCL ) and mantle cell lymphoma ( MCL ) cells, including those highly resistant to bortezomib. Co‐administration of PCI ‐32765/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre‐ or activated B‐cell‐like‐ DLBCL cells and in MCL cells. These events were accompanied by marked AKT and nuclear factor ( NF )‐κB ( NFKB 1) inactivation, down‐regulation of Mcl‐1 (MCL1), Bcl‐ xL ( BCL 2L1), and XIAP , and enhanced DNA damage (e.g., γH2A.X formation) and endoplasmic reticulum ( ER ) stress. Similar interactions were observed in highly bortezomib‐resistant DLBCL and MCL cells, and in primary DLBCL cells. In contrast, PCI ‐32765/bortezomib regimens displayed minimal toxicity toward normal CD 34 + bone marrow cells. Transfection of DLBCL cells with a constitutively active AKT construct attenuated AKT inactivation and significantly diminished cell death, whereas expression of an NF ‐κB “super‐repressor” (IκBα ser34/36 ) increased both PCI ‐32765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant‐negative eIF 2α construct were resistant to this regimen. Finally, combined exposure to PCI ‐32765 and bortezomib resulted in more pronounced and sustained reactive oxygen species ( ROS ) generation, and ROS scavengers significantly diminished lethality. Given promising early clinical results for PCI‐32765 in DLBCL and MCL , a strategy combining BTK /proteasome inhibitor warrants attention in these malignancies.