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Temozolomide-mediated DNA methylation in human myeloid precursor cells: differential involvement of intrinsic and extrinsic apoptotic pathways.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Wang, Haiyan Cai, Shanbao Ernstberger, Aaron Bailey, Barbara J. Wang, Michael Zhuo Cai, Wenjing Goebel, William S. Czader, Magdalena B. Crean, Colin Daniel Suvannasankha, Attaya Shokolenkoc, Inna Wilson, Glenn L. Baluyut, Arthur R. Mayo, Lindsey D. Pollok, Karen E. |
| Copyright Year | 2013 |
| Abstract | PURPOSE An understanding of how hematopoietic cells respond to therapy that causes myelosuppression will help develop approaches to prevent this potentially life-threatening toxicity. The goal of this study was to determine how human myeloid precursor cells respond to temozolomide (TMZ)-induced DNA damage. EXPERIMENTAL DESIGN We developed an ex vivo primary human myeloid precursor cells model system to investigate the involvement of cell-death pathways using a known myelosuppressive regimen of O(6)-benzylguanine (6BG) and TMZ. RESULTS Exposure to 6BG/TMZ led to increases in p53, p21, γ-H2AX, and mitochondrial DNA damage. Increases in mitochondrial membrane depolarization correlated with increased caspase-9 and -3 activities following 6BG/TMZ treatment. These events correlated with decreases in activated AKT, downregulation of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT), and increased cell death. During myeloid precursor cell expansion, FAS/CD95/APO1(FAS) expression increased over time and was present on approximately 100% of the cells following exposure to 6BG/TMZ. Although c-flipshort, an endogenous inhibitor of FAS-mediated signaling, was decreased in 6BG/TMZ-treated versus control, 6BG-, or TMZ alone-treated cells, there were no changes in caspase-8 activity. In addition, there were no changes in the extent of cell death in myeloid precursor cells exposed to 6BG/TMZ in the presence of neutralizing or agonistic anti-FAS antibodies, indicating that FAS-mediated signaling was not operative. CONCLUSIONS In human myeloid precursor cells, 6BG/TMZ-initiated apoptosis occurred by intrinsic, mitochondrial-mediated and not extrinsic, FAS-mediated apoptosis. Human myeloid precursor cells represent a clinically relevant model system for gaining insight into how hematopoietic cells respond to chemotherapeutics and offer an approach for selecting effective chemotherapeutic regimens with limited hematopoietic toxicity. |
| File Format | PDF HTM / HTML |
| DOI | 10.1158/1078-0432.CCR-12-2671 |
| PubMed reference number | 23536437 |
| Journal | Medline |
| Volume Number | 19 |
| Issue Number | 10 |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/19/10/2699.full.pdf |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/early/2013/05/01/1078-0432.CCR-12-2671.full.pdf |
| Alternate Webpage(s) | https://doi.org/10.1158/1078-0432.CCR-12-2671 |
| Journal | Clinical cancer research : an official journal of the American Association for Cancer Research |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
