Cell growth and topoisomerase IIα inhibitory activity of the bacterial metabolites kinamycin C and kinamycin A
Notice bibliographique
Résumé
Proc Amer Assoc Cancer Res, Volume 46, 2005 2392 The antibiotics kinamycin C (KC) and kinamycin A (KA) are naturally occurring bacterial metabolites isolated from Streptomyces murayamaensis that contain an unusual and potentially reactive diazo side chain. Although the antimicrobial activity of the kinamycins has been described, the mechanism of inhibition of cell growth by these compounds is unknown. Our results show that KC and KA strongly inhibit the growth of the human erythroleukemic K562 cells ( IC 50 of 0.2 and 0.3 μM, respectively). A short drug treatment of the cells also resulted in strong growth inhibition indicating a rapid onset of action. KC rapidly induced apoptosis in K562 cells as measured by flow cytometry using annexin V-FITC staining and PI staining of DNA content. When synchronized CHO cells were treated with KA, the cells were able to exit G0 and traverse the first G2/M phase, but were not able to enter the second G2/M phase. KC and KA also inhibited the catalytic activity of purified human DNA topoisomerase IIα (topo II), but not that of topoisomerase I. Preincubation of KC with topo II reduced topo II activity, indicating that KC may have inhibited topo II through a direct reaction. The inhibitory activities of KC and KA were modulated by the presence of dithiothreitol (DTT) in the assay mixture as an increase in the DTT concentration (from 0.1 to 250 μM) in the reaction mixture increased the IC 50 of KC from 9 to 108 μM, and of KA from 8 to 66 μM. Based on the ability of DTT to partially protect topo II from inhibition by these compounds, the possibility that these compounds inhibit by reacting with critical thiol groups on topo II is being explored. Neither KC nor KA were able to cross-link DNA, nor did they bind to DNA, which indicated that these compounds did not act directly on DNA. KA and KC were also examined for their ability to stabilize a DNA-topo II covalent complex and act as a topoisomerase IIα poison by measuring their ability to cleave pBR322 DNA to produce linear DNA. Neither KA nor KC induced DNA cleavage and, thus, it was concluded that they did not act as topo II poisons. Also the growth inhibitory effects of KC and KA on K562 and K/VP.5 cells (containing one-fifth the topo II content of the parental K562 cells) were not significantly different, a result that is also consistent with these compounds exerting their activity by mechanisms distinct from topo II poisoning. In summary these results indicate that even though KC and KA inhibited topo II catalytic activity, this may not be the mechanism by which they inhibited cell growth. Support: CIHR and a Canada Research Chair in Drug Development to BH, NSERC through a Discovery Grant to GID and ROI CA90787 to JCY.
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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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
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 ».