Schedule-dependent synergy between the heat shock protein 90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin and doxorubicin restores apoptosis to p53-mutant lymphoma cell lines
| Autor: | Adrian Wiestner, Mollie H. Wright, Christin L. Hanigan, Bheru Gandhi, Lyuba Varticovski, Ana I. Robles, Steven S. Feis |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Programmed cell death Lymphoma Lactams Macrocyclic Immunoblotting Apoptosis Biology Drug Administration Schedule Annexin Heat shock protein Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Benzoquinones Humans Doxorubicin HSP90 Heat-Shock Proteins Cytotoxicity Cell Cycle Drug Synergism Cell cycle Drug interaction Oncology Drug Resistance Neoplasm Mutation Cancer research Tumor Suppressor Protein p53 medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 12(21) |
| ISSN: | 1078-0432 |
| Popis: | Purpose: Loss of p53 function impairs apoptosis induced by DNA-damaging agents used for cancer therapy. Here, we examined the effect of the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) on doxorubicin-induced apoptosis in lymphoma. We aimed to establish the optimal schedule for administration of both drugs in combination and the molecular basis for their interaction. Experimental Design: Isogenic lymphoblastoid and nonisogenic lymphoma cell lines differing in p53 status were exposed to each drug or combination. Drug effects were examined using Annexin V, active caspase-3, cell cycle, and cytotoxicity assays. Synergy was evaluated by median effect/combination index. Protein expression and kinase inhibition provided insight into the molecular mechanisms of drug interaction. Results: Presence of mutant p53 conferred increased survival to single agents. Nevertheless, DMAG showed synergistic toxicity with doxorubicin independently of p53 status. Synergy required exposure to doxorubicin before DMAG. DMAG-mediated down-regulation of CHK1, a known HSP90 client, forced doxorubicin-treated cells into premature mitosis followed by apoptosis. A CHK1 inhibitor, SB-218078, reproduced the effect of DMAG. Administration of DMAG before doxorubicin resulted in G1-S arrest and protection from apoptosis, leading to additive or antagonistic interactions that were exacerbated by p53 mutation. Conclusions: Administration of DMAG to doxorubicin-primed cells induced premature mitosis and had a synergistic effect on apoptosis regardless of p53 status. These observations provide a rationale for prospective clinical trials and stress the need to consider schedule of exposure as a critical determinant of the overall response when DMAG is combined with chemotherapeutic agents for the treatment of patients with relapsed/refractory disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|