Abstract A188: Proapoptotic <i>versus</i> prosurvival function of the MAP kinase p38 induced by HDAC inhibitor in hematological malignant cells
Bibliographic record
Abstract
Abstract Histone deacetylase inhibitors (HDACi) have recently emerged as promising anticancer agents. However, the mechanisms by which HDAC inhibitors arrest proliferation and induce apoptosis in tumor cells is far from clear. Activation of the stress MAP kinases and induction of DNA damage by different HDACi have been reported, however, the potential role of the MAP kinase p38 in the antitumor activity of these drugs has not been described. P38 is known to be activated independently or downstream of DNA damage. The purpose of this study was to elucidate the mechanisms by which the HDACi vorinostat (Zolinza®) triggers apoptosis in haematological malignant cells. We show that DNA damage as well as activation of p38 occurs relatively early in acute myeloid leukemia (AML) cell lines after treatment with vorinostat. Using comet assays, we detected direct evidence of early DNA damage and western blotting revealed induction of the DNA damage response proteins ATM and Chk2. We performed cell cycle analysis, and observed within the vorinostat-treated AML cell population, cells exiting G1 and accumulating in the G2-M phase of the cell cycle, where they subsequently underwent apoptosis. Notably, downregulation of p38 by shRNA or inhibition of p38 and β activity by the inhibitor SB203580 significantly decreased both G2-M accumulation and apoptosis induced by vorinostat, indicating a pro-apoptotic p38 function. Interestingly, several other HDACi tested all induced p38 activation but, depending on the HDACi, this activation was found to be either pro or antiapoptotic. The short-chain fatty acid sodium butyrate (NaB) requires p38 for induction of apoptosis, like vorinostat. On the other hand, LBH589, from the structural class encompassing vorinostat, does not depend on p38 for induction of apoptosis. Furthermore, p38 serves as a pro-survival signal when induced by the benzimide MGCD0103. In conclusion, we have shown that vorinostat-induced apoptosis in AML cells is preceded by generation of DNA damage and accumulation of cells in the G2-M phase of the cell cycle. Further, G2-M arrest and apoptosis induction (but not DNA damage) by vorinostat requires activation of the p38 MAP kinase, which is not the case for all HDACi. Therefore, a better understanding of the role of p38 MAPK in the action of specific HDACi may help in the development of rational combination regimes including these targeted agents. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A188.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".