New aryl chloroethylureas derivatives that inhibit cancer cell growth target thioredoxin-1 and abolish its nuclear translocation
Bibliographic record
Abstract
AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 3208 Aryl Chloroethylureas (CEU) are protein “soft” alkylating agents displaying potent antineoplastic properties. We previously showed that CEU alkylate β-tubulin and interfered with the microtubule network polymerization process. Some CEU such as CEU-025 don’t alkylate β-tubulin but remains cytotoxic. The objective of our research was to identify the protein(s) targeted by CEU-025 and to study its antiproliferative mechanism of action. Two dimension gel analysis of protein extracted from MDA-MB 231 cells exposed to [14C]-CEU-025 revealed a radioactive 14-kDa protein. Mass spectrometry has identified the protein as thioredoxin-1 (Trx-1), a major redox signalling protein catalyzing the reduction of protein cysteinyl residues. Western blot analysis with a specific Trx-1 antibody confirmed that Trx-1 is target by CEU-025. Other CEU derivatives were found to bind covalently to Trx-1 as demonstrated by competition assays using [14C]-CEU-025. Unexpectedly, Trx-1 exposed to CEU-025 does not decrease significantly its catalytic activity to reduce disulphide bonds in vivo and in vitro as determined using the insulin reduction assay. CEU-025, in contrast to iodoacetic acid, doesn’t alkylated the Trx-1 cysteinyl residues as confirmed using the diamide-mediated oxidation assay. Trx-1, upon its translocation to the nucleus, is known to increase the transcriptional activity of various transcription factors. Therefore, we studied the intracellular distribution of Trx-1 in HT1080, M21 and MCF-7 cells, in response to CEU-025 exposure. CEU-025 inhibits drastically the nuclear translocation of Trx-1 in these cancer cell lines. In contrast, neither exposure with classical antineoplastic such as paclitaxel, cisplatin, daunorubicin or chlorambucil nor with the Trx-1 inhibitor PX-12 inhibited Trx-1 nuclear translocation. We hypothesized that CEU-025-mediated Trx-1 nuclear depletion dramatically decreased the expression level of various genes. To assess this, microarray experiments were performed on M21 cells exposed or not to CEU-025. Preliminary analysis indicated that several genes are down regulated in response to the drug. Ongoing RT-PCR expression analyses are being carried out to confirm the identity and the expression changes observed by microarray experiments.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".