Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models
| Autor: | Francesco Colotta, Veronica Patton, Roberta Ceruti, Marina Ciomei, Josée Golay, Martino Introna, Alessandro Rambaldi, Rachele Alzani, Enrico Pesenti, Olga Pedrini, Alessia Casolaro, Clara Albanese |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Blotting Western CD34 Antineoplastic Agents Apoptosis Mice SCID Biology Pharmacology Peripheral blood mononuclear cell Inhibitory Concentration 50 Mice In vivo Cell Line Tumor Genetics medicine Cytotoxic T cell Animals Humans Molecular Biology Leukemia Cell Cycle Cell Biology Hematology medicine.disease Immunohistochemistry In vitro Cyclin-Dependent Kinases Haematopoiesis Disease Models Animal Stem cell Drug Screening Assays Antitumor |
| Zdroj: | Experimental hematology. 38(4) |
| ISSN: | 1873-2399 |
| Popis: | The aim of the work was to determine and characterize, in vitro and in vivo, the therapeutic activity of PHA-793887, a new potent pan-cdk inhibitor, in the context of hematopoietic neoplasms.Thirteen leukemic cell lines bearing different cytogenetic abnormalities and normal hematopoietic cells were used in cytotoxicity and colony assays. The drug activity at the molecular level was analyzed by Western blotting. PHA-793887 was also tested in vivo in several leukemia xenograft models.PHA-793887 was cytotoxic for leukemic cell lines in vitro, with IC(50) ranging from 0.3 to 7 microM (mean: 2.9 microM), regardless of any specific chromosomal aberration. At these doses, the drug was not cytotoxic for normal unstimulated peripheral blood mononuclear cells or CD34(+) hematopoietic stem cells. Interestingly, in colony assays PHA-793887 showed very high activity against leukemia cell lines, with an IC(50)0.1 microM (mean: 0.08 microM), indicating that it has efficient and prolonged antiproliferative activity. PHA-793887 induced cell-cycle arrest, inhibited Rb and nucleophosmin phosphorylation, and modulated cyclin E and cdc6 expression at low doses (0.2-1 microM) and induced apoptosis at the highest dose (5 microM). It was also effective in vivo in both subcutaneous xenograft and primary leukemic disseminated models that better mimic naturally occurring human disease. Interestingly, in one disseminated model derived from a relapsed Philadelphia-positive acute lymphoid leukemia patient, PHA-793887 showed strong therapeutic activity also when treatment was started after establishment of high disease burden.We conclude that PHA-793887 has promising therapeutic activity against acute leukemias in vitro and in vivo. |
| Databáze: | OpenAIRE |
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