MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells.
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| Abstract |
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.
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| Authors | Llorenç Coll-Mulet, Daniel Iglesias-Serret, Antonio F Santidrián, Ana M Cosialls, Mercè de Frias, Esther Castaño, Clara Campàs, Montserrat Barragán, Alberto Fernández de Sevilla, Alicia Domingo, Lyubomir T Vassilev, Gabriel Pons, Joan Gil |
| Journal | Blood (Blood) Vol. 107 Issue 10 Pg. 4109-14 (May 15 2006) ISSN: 0006-4971 [Print] United States |
| PMID | 16439685 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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