Abstract 3060: Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib and carfilzomib
Bibliographic record
Abstract
Abstract Bortezomib and carfilzomib are anticancer drugs that target the proteasomal system. Case reports indicate that the use of these drugs can result in cardiotoxicity. These drugs may also be used in combination with doxorubicin, which is itself cardiotoxic. Thus, in order to determine the mechanism of this cardiotoxicity studies were undertaken using a neonatal rat myocyte primary cell model. Using LDH release as a measure of damage in the myocyte model we showed that even brief exposure (6 h) to submicromolar concentrations of bortezomib resulted in significant myocyte damage. Carfilzomib was slightly less toxic and displayed myocyte damage in the low micromolar concentration range. Utilizing a fluorogenic substrate both bortezomib and carfilzomib inhibited the chymotrypsin-like proteasomal activity of myocyte lysate in the submicromolar concentration range. The inhibition kinetics were consistent with formation of an essentially irreversible covalent complex at the active site. Bortezomib irreversibly inhibited proteasomal activity about four-fold faster than carfilzomib. Thus, the reduced toxicity of carfilzomib may be due to its slower inhibition kinetics. A brief pre-exposure (6 h) of myocytes to low non-toxic nanomolar concentrations of bortezomib greatly increased doxorubicin-mediated damage. The doxorubicin cardioprotective agent dexrazoxane partially protected the myocytes from doxorubicin treatment and from bortezomib plus doxorubicin treatment under these conditions. However, at slightly toxic bortezomib concentrations dexrazoxane offered little protection against bortezomib plus doxorubicin treatment. Bortezomib, at least over short times, did not induce oxidative damage in myocytes as measured with a fluorogenic DCF assay. Likewise, a 6 h bortezomib treatment did not affect the mitochondrial membrane potential of myocytes as measured in a JC-1 ratiometric assay. In conclusion both bortezomib and carfilzomib are potently toxic to myocytes at submicromolar concentrations, likely through their ability to irreversibly inhibit myocyte proteasomal activity. Support: CIHR; a Canada Research Chair in Drug Development. Citation Format: Brian B. Hasinoff, Xing Wu, Daywin Patel. Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib and carfilzomib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3060.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".