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Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/Reed-Sternberg cells
- Source :
- Leukemia. 21(4)
- Publication Year :
- 2007
-
Abstract
- The status of the p53 pathway in classical Hodgkin lymphoma (cHL) remains unclear, and a lack of proven TP53 mutations contrasts with often high expression levels of p53 protein. In this study, we demonstrate that pharmacologic activation of the p53 pathway with the murine double minute 2 (MDM2) antagonist nutlin-3 in Hodgkin lymphoma-derived cell lines leads to effective apoptosis induction and sensitizes the cells to other anticancer drugs. Cells with mutant p53 are resistant to nutlin-3, but sensitive to geldanamycin, a pharmacologic inhibitor of heat shock 90 kDa protein (HSP90), indicating that HSP90 inhibition can induce apoptosis in a p53-independent manner. Conversely, cells with defects in the HSP90/nuclear factor-kappa B pathway expressing wild-type p53 are more resistant to geldanamycin, but still sensitive to nutlin-3. Our results suggest that selective activation of p53 by MDM2 antagonists as a single agent or in combination with conventional chemotherapeutics and/or inhibitors of p53-independent survival pathways may offer effective treatment options for patients with cHL. Importantly, because nutlins and HSP90 inhibitors are non-genotoxic agents, their use might offer a means to reduce the genotoxic burden of current chemotherapeutic regimens.
- Subjects :
- Cancer Research
Programmed cell death
Tumor suppressor gene
Transcription, Genetic
Cell Survival
Lactams, Macrocyclic
Apoptosis
Biology
Piperazines
chemistry.chemical_compound
Mice
Cell Line, Tumor
polycyclic compounds
medicine
Benzoquinones
Animals
Humans
RNA, Small Interfering
Reed-Sternberg Cells
Antibiotics, Antineoplastic
Imidazoles
Hematology
Nutlin
Geldanamycin
medicine.disease
Hsp90
Hodgkin Disease
Oncology
chemistry
Reed–Sternberg cell
Cancer research
biology.protein
Mdm2
Tumor Suppressor Protein p53
Subjects
Details
- ISSN :
- 08876924
- Volume :
- 21
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....b51ba64da074182db03399e02567ee49