MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells.
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived CD5(+) B lymphocytes. Several drugs currently used in the therapy of B-CLL act, at least partially, through activation of the p53 pathway. Recently, nongenotoxic small-molecule activators of p53, the nutlins, have been developed that inhibit p53-MDM2 binding. We have investigated the antitumor potential of nutlin-3 in B-CLL and find that it can activate the p53 pathway and effectively induce apoptosis in cells with wild-type p53, including cells with dysfunctional ataxia telangiectasia mutated, but not mutant p53. Nutlin-3 stabilized p53 and induced p53 target genes, including MDM2, p21(CIP1), PUMA, BAX, PIG3, and WIG1. Nutlin-3 synergized with the genotoxic drugs doxorubicin, chlorambucil, and fludarabine, but not with acadesine, which induces p53-independent apoptosis. Normal human T cells showed lower sensitivity to nutlin-3 than B-CLL cells and no synergism with the genotoxic drugs. These results suggest that MDM2 antagonists alone or in combination with chemotherapeutic drugs may offer a new treatment option for B-CLL.
Coll-Mulet
Llorenç
L
Departament de Ciències Fisiològiques II, IDIBELL-Universitat de Barcelona, Campus de Bellvitge, Pavelló de Govern, 4a planta, E-08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Iglesias-Serret
Daniel
D
Santidrián
Antonio F
AF
Cosialls
Ana M
AM
de Frias
Mercè
M
Castaño
Esther
E
Campàs
Clara
C
Barragán
Montserrat
M
de Sevilla
Alberto Fernández
AF
Domingo
Alicia
A
Vassilev
Lyubomir T
LT
Pons
Gabriel
G
Gil
Joan
J
D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D018956:CD5 Antigens; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D015703:Antigens, CD; D000970:Antineoplastic Agents; D018956:CD5 Antigens; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2