Abstract
Aim: Ataxia telangiectasia (A-T) is an autosomal recessive disease in humans caused by mutations in the Atm (A-T mutated) gene. The disease involves multiple organ systems, and is associated with a high incidence of leukemias and lymphomas that develop in childhood. We have reported previously that thymic lymphoma development in Atm knockout (Atm-/-) mice is associated with elevated spontaneous DNA synthesis in thymocytes, and that dexamethasone (Dex) attenuates the elevated DNA synthesis and prevents thymic lymphoma development. The primary objectives of the present study were (1) to investigate possible mechanisms underlying the tumor-suppressing effect of Dex on Atm-/- thymic lymphoma cells, and (2) to determine whether Dex is an effective tumor-suppressing treatment in mice bearing transplanted Atm-/- thymic tumors. Methods: Establishment of a number of Atm-/-thymic lymphoma (ATL) cell lines from Atm-/- mice, cell proliferation assays, cell cycle analyses, Western blotting and Hoechst nuclear staining were used to analyze the effects of Dex on Aim-/- thymic lymphoma cells. Atm-/- tumor cells were transplanted into the right flanks of Atm+/+ mice prior to the initiation of Dex treatment. Results: Atm-/- tumor cells were highly sensitive to Dex, both in culture and in vivo as ectopic tumors in mice. In cultured ATL-1 cells, Dex induced apoptosis, arrested the cell cycle at the G1 phase and downregulated NF-κB and multiple cell cycle regulators, while upregulating the NF-κB inhibitor IκBα. In Atm+/ + mice transplanted subcutaneously with ATL-1 cells, tumor growth was either prevented completely or significantly suppressed by Dex treatment. Conclusions: Our findings identify potential mechanisms by which Dex affects the proliferation and survival of ATL-1 cells in culture, and provide evidence that Dex can suppress the proliferation of Aim-/- thymic lymphoma cells growing in the body. Together these results add to our earlier published data suggesting that the cellular pathways regulated by Dex may be promising therapeutic targets for prevention and treatment of thymic lymphomas in A-T individuals.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 203-212 |
| Number of pages | 10 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 55 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2005 |
Funding
Acknowledgements This work was supported in part by grants from the A-T Children’s Project (Deerfield Beach, FL), A-T Project (Austin, TX), NIEHS Center grant ES07784, and the National Cancer Institute (M.D. Anderson Core Grant CA16672). We thank Vanessa Edwards for her assistance in preparing the manuscript, Dr. David Johnson for critical review of the manuscript, and Dr. Jacqueline Dudley for the gift of the ASL-1 cell line. We are also most grateful to Mr. Kent Claypool for assistance with flow cytometry analysis, and to Ms. Lifang Zhang and Ms. Jennifer Voorhees for technical assistance.
Keywords
- Apoptosis
- Atm gene knockout mice
- Cell cycle
- Dexamethasone
- Lymphoid malignancy
ASJC Scopus subject areas
- Pharmacology (medical)
- Oncology
- Cancer Research
- Toxicology
- Pharmacology
