Abstract A146: The role of cystine transport in darinaparsin-induced cell death
Notice bibliographique
Résumé
Abstract Darinaparsin (ZIO-101; S-dimethylarsino-glutathione; Dar) is a promising novel organic arsenical, currently undergoing clinical studies in various malignancies. Dar is synthesized by conjugating dimethylarsenic (DMA) to glutathione (GSH) and shows enhanced activity as compared to arsenic trioxide (ATO). Dar induces more intracellular arsenic accumulation, oxidative stress (OS) and cell death than ATO. However, Dar has a maximum tolerated dose that is 35-fold higher than ATO. The mechanisms responsible for the lower toxicity and higher anti-tumor efficacy associated with Dar remains to be elucidated. Here, we propose a mechanism for Dar import that might, at least partially, explain the enhanced efficacy. Preliminary results show that both ATO and Dar induce the expression of the cystine importer xCT and that high levels of xCT expression correlates with high sensitivity to Dar, as shown in a NCI60 panel. The cystine/cysteine redox cycle consists of cystine uptake, intracellular reduction to cysteine which is secreted into the extracellular space where it is oxidized back to cystine. Intracellular cysteine (Cys-SH) can be used for the synthesis of GSH, the major intracellular OS scavenger. We find that increased extracellular concentration of L-cysteine or equivalent thiols during Dar treatment inhibits intracellular arsenic accumulation, measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), as well as apoptosis, assessed by propidium iodide staining quantitated by flow cytometry. Thus, we hypothesized that L-cysteine or equivalent thiols might prevent Dar import. GSH itself is not imported in the cell, so we thought it unlikely that darinaparsin would enter the cell without being somehow modified. Structural analysis of darinaparsin reveals putative break-down products: dimethylarsino-cysteine (DMAC), dimethylarsenic III (DMA III) and dimethylarsenic V (DMA V). ICP-MS experiments showed that treatment with DMA III and DMA V does not lead to significant intracellular accumulation of arsenic, and correlates with their inability to induce cell death. However, DMAC is very similar to Dar in terms of intracellular accumulation of arsenic, G2/M arrest and cell death. As with Dar, thiols were able to inhibit DMAC-induced cell death. In summary, we hypothesize that darinaparsin gets transformed extracellularly into DMAC, which is imported via xCT or another cystine/cysteine importing system. Cells respond to arsenic-induced OS by increasing cystine uptake, which may selectively increase the anti-cancer activity of Dar. The fact that cancer cells, under a high OS state, have an increase need for GSH, i.e. for cystine, might explain the fewer systemic toxicities reported with Dar. Moreover, cystine/cysteine importers may be valuable biomarkers to predict Dar sensitivity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A146.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».