alpha-chymotrypsin and Lymphoma--Large-B-Cell--Diffuse

Interactions between histone deacetylase inhibitors (HDACIs) and the novel proteasome inhibitor carfilzomib (CFZ) were investigated in GC- and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cells. Coadministration of subtoxic or minimally toxic concentrations of CFZ) with marginally lethal concentrations of HDACIs (vorinostat, SNDX-275, or SBHA) synergistically increased mitochondrial injury, caspase activation, and apoptosis in both GC- and ABC-DLBCL cells. These events were associated with Jun NH2-terminal kinase (JNK) and p38MAPK activation, abrogation of HDACI-mediated nuclear factor-kappaB activation, AKT inactivation, Ku70 acetylation, and induction of gammaH2A.X. Genetic or pharmacologic JNK inhibition significantly diminished CFZ/vorinostat lethality. CFZ/vorinostat induced pronounced lethality in 3 primary DLBCL specimens but minimally affected normal CD34(+) hematopoietic cells. Bortezomib-resistant GC (SUDHL16) and ABC (OCI-LY10) cells exhibited partial cross-resistance to CFZ. However, CFZ/vorinostat dramatically induced resistant cell apoptosis, accompanied by increased JNK activation and gammaH2A.X expression. Finally, subeffective vorinostat doses markedly increased CFZ-mediated tumor growth suppression and apoptosis in a murine xenograft OCI-LY10 model. These findings indicate that HDACIs increase CFZ activity in GC- and ABC-DLBCL cells sensitive or resistant to bortezomib through a JNK-dependent mechanism in association with DNA damage and inhibition of nuclear factor-kappaB activation. Together, they support further investigation of strategies combining CFZ and HDACIs in DLBCL.

Topics: Animals; Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Cell Cycle; Chymotrypsin; DNA Damage; Drug Resistance, Neoplasm; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; In Vitro Techniques; JNK Mitogen-Activated Protein Kinases; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Nude; Mitochondria; NF-kappa B; Oligopeptides; Protease Inhibitors; Proteasome Inhibitors; Pyrazines; Vorinostat; Xenograft Model Antitumor Assays

A retrospective study of 76 primary gastrointestinal lymphomas utilizing an avidin: biotinylated horseradish peroxidase complex (ABC) technique demonstrated 22 B-cell lymphomas, including two associated with alpha-heavy chain disease. Seven cases were classified as true histiocytic lymphomas based on a positive reaction for one or more of three histiocytic enzyme markers utilized, predominantly alpha-1-antitrypsin and alpha-1-antichymotrypsin. However, in 20 cases, an intense admixture of reactive histiocytes was noted and these cells stained preferentially for the enzyme, lysozyme. Twenty cases, which stained for both kappa and lambda light chains and positively or negatively for albumin, could not be classified and 27 cases failed to stain with any of the antisera utilized.

Topics: alpha 1-Antichymotrypsin; alpha 1-Antitrypsin; Antibodies; B-Lymphocytes; Chymotrypsin; Gastrointestinal Neoplasms; Heavy Chain Disease; Histocytochemistry; Humans; Immunoenzyme Techniques; Immunoglobulin alpha-Chains; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Muramidase

Vertical studies indicate that, in general, acute phase reactant proteins (APRP) reflect disease activity in both Hodgkin's disease and non-Hodgkin's lymphoma. Longitudinal studies of the selected APRP profile demonstrate the following: 1. The stable profile is characteristic of remission. 2. Considerable elevation of APRPs coincides with relapsed disease. 3. An unstable profile is a feature of relapsing disease and may give early warning of relapse. 4. Patients responding inadequately to treatment frequently have unstable APRP profiles.

Topics: Adult; alpha 1-Antitrypsin; C-Reactive Protein; Chymotrypsin; Female; Glycoproteins; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Middle Aged; Orosomucoid