Potential pathogenetic implications of cyclooxygenase-2 overexpression in B chronic lymphoid leukemia cells.
Evidence suggests that cyclooxygenase-2 (COX-2) increases tumorigenic potential by promoting resistance to apoptosis. Because B chronic lymphoid leukemia (B-CLL) cells exhibit a defective apoptotic response, we analyzed CD19(+) B lymphocytes purified from the peripheral blood of B-CLL patients. Microarray analysis showed a variable (up to 38-fold) increase in the steady-state mRNA levels of COX-2 in B-CLL lymphocytes compared with normal CD19(+) B lymphocytes. The up-regulation of COX-2 in B-CLL cells was confirmed by reverse transcriptase-polymerase chain reaction and Western blot analyses. Moreover, immunohistochemical analysis of B-CLL bone marrow infiltrates confirmed clear expression of COX-2 in leukemic cells. Ex vivo treatment with the COX-2 inhibitor NS-398 significantly decreased the survival of leukemic cells by increasing the rate of spontaneous apoptosis in 13 of 16 B-CLL samples examined, but it did not affect the survival of normal lymphocytes. Pretreatment with NS-398 significantly potentiated the cytotoxicity induced by chlorambucil in 8 of 16 B-CLL samples examined. Moreover, although recombinant tumor necrosis factor-related apoptosis inducing ligand (TRAIL)/Apo2L showed little cytotoxic effect in most B-CLL samples examined, pretreatment with NS-398 sensitized 8 of 16 B-CLL samples to TRAIL-induced apoptosis. Taken together, our data indicate that COX-2 overexpression likely represents an additional mechanism of resistance to apoptosis in B-CLL and that pharmacological suppression of COX-2 might enhance chemotherapy-mediated apoptosis.
Secchiero
Paola
P
Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Italy. secchier@mail.umbi.umd.edu
Barbarotto
Elisa
E
Gonelli
Arianna
A
Tiribelli
Mario
M
Zerbinati
Carlotta
C
Celeghini
Claudio
C
Agostinelli
Claudio
C
Pileri
Stefano A
SA
Zauli
Giorgio
G
D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000201:enzymology; D002455:Cell Division; D051546:Cyclooxygenase 2 / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008214:Lymphocytes / Q000201:enzymology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging
D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human