Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells.
OBJECTIVE
Antiapoptotic Bcl-2 is overexpressed in most cases of chronic lymphocytic leukemia (CLL). The inhibition of the antiapoptotic Bcl-2 proteins is an attractive strategy for either restoring normal apoptotic process in cancer cells or making these cells more susceptible to conventional chemotherapy. We studied the effect of Bcl-2 inhibitors on the viability of cells from CLL and other mature B-cell neoplasms.


METHODS
We studied the cytotoxic effects of four nonpeptidic cell-permeable Bcl-2 inhibitors (HA14-1, antimycin A, GX15-003, and GX15-070) on B cells from patients with CLL, mantle cell lymphoma (MCL), and splenic marginal zone lymphoma (SMZL). Moreover, we analyzed the effect of these inhibitors in combination with fludarabine or chlorambucil.


RESULTS
HA14-1 induced apoptosis with an EC50 lower than 50 microM in 26 of the 36 CLL samples analyzed. The mean EC50 for these sensitive patients was 23 +/- 2 microM. Antimycin A induced apoptosis in 13 of the 18 CLL samples analyzed. Both HA14-1 and antimycin A induced cytochrome c release from mitochondria and caspase-3 activation. Moreover, HA14-1 induced apoptosis in peripheral cells from MCL and SMZL. HA14-1 also induced apoptosis in CLL samples with alterations in p53 or ATM. Finally, GX compounds induced apoptosis in B cells from 9 of the 11 CLL samples tested. The combination of either HA14-1, antimycin A, or GX compounds with fludarabine or chlorambucil had additive cytotoxic effects on CLL cells.


CONCLUSIONS
Bcl-2 inhibitors induce apoptosis in CLL cells ex vivo and could be used in CLL as monotherapy or given in combination with current chemotherapy.
Campàs
Clara
C
Departament de Ciències Fisiològiques II, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
Cosialls
Ana M
AM
Barragán
Montserrat
M
Iglesias-Serret
Daniel
D
Santidrián
Antonio F
AF
Coll-Mulet
Llorenç
L
de Frias
Mercè
M
Domingo
Alicia
A
Pons
Gabriel
G
Gil
Joan
J
D000968:Antimycin A / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007211:Indoles; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology*; D013160:Splenic Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D001578:Benzopyrans; D007211:Indoles; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D000968:Antimycin A; C520962:obatoclax