P5434P300-mediated inactivation of p53 protects against doxorubicin-induced cardiotoxicity
Bibliographic record
Abstract
Abstract Introduction Doxorubicin is amongst the most widely prescribed chemotherapy drugs due to its effectiveness in cancer treatment. However, progressive treatment using doxorubicin severely increases the risk of congestive heart failure. Mechanistically, researchers have shown that doxorubicin (i) intercalates into DNA and disrupts topoisomerase-II-mediated DNA repair and (ii) generates free radicals which then causes damage to cellular membranes, DNA, and proteins. Ultimately these cellular insults induce cardiomyocyte (CM) death mediated by the tumour suppressor, p53. Currently, there are no clinically applicable preventative treatments for doxorubicin-induced cardiotoxicity and so, extensive research is being done in discovering a potential therapy. One such candidate is curcumin – a natural polyphenol compound non-toxic to humans. We have previously demonstrated that curcumin inhibits lysine acetyltransferase activity of p300, therefore reducing both histone and non-histone protein acetylation. To induce CM death, p53 requires acetylation by p300. Therefore, we hypothesize that curcumin protects against doxorubicin-induced CM death and cardiotoxicity via p300-mediated inactivation of p53. Methods Rat H9c2 cardiomyoblast cells were cultured and treated with a 2.5 μM dose of doxorubicin for 16 hours. One group of cells were pre-treated with curcumin (15μM) 4 hours prior to doxorubicin treatment, and controls were cultured with only diluent added. Following treatment, the cells were harvested for total protein. At end point, we performed immunoblotting to measure protein expression of key proteins involved in DNA damage (y-H2A.X, p53), and apoptosis (cleaved-Caspase 3). Results Our findings show that following doxorubicin treatment, p53 expression was significantly increased (p<0.001), confirming its role in doxorubicin-associated cardiotoxicity. Furthermore, doxorubicin was associated with increased DNA-damage as evidenced by increased expression and activation of DNA double-stranded breaks (DSBs) marker, y-H2A.X (p<0.001). Elevated levels of DNA-damage were further associated with significantly increased doxorubicin-induced apoptosis as measured by immunoblotting for cleaved-Caspase 3 (p<0.001). However, DNA-damage and apoptosis were attenuated by pre-treatment of cells with curcumin. Curcumin treatment led to a significant decrease in both y-H2A.X (p<0.01) and cleaved-Caspase 3 (p<0.01) expression compared to cells treated with only doxorubicin. Conclusions Our data provides the first evidence that curcumin protects against doxorubicin-induced apoptosis in rat cardiomyoblast cells in vitro. Further studies are warranted in vivo to confirm the potential of curcumin as a cardio-protective drug. Curcumin is a natural compound with little to no side-effects in humans, therefore our finding may provide a novel therapeutic target and treatment approach for doxorubicin-associated cardiotoxicity. Acknowledgement/Funding Heart & Stroke Foundation of Canada
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".