Insight into the strong inhibitory action of salt on activity of neocarzinostatin
| Autor: | Christopher G. Sudhahar, Huang Hsien Li, Der Hang Chin, Pei Yin Tsai |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Drug
DNA damage media_common.quotation_subject Clinical Biochemistry Pharmaceutical Science Drug action Sodium Chloride Biochemistry chemistry.chemical_compound Zinostatin Drug Discovery Enediyne medicine Molecular Biology media_common chemistry.chemical_classification Neocarzinostatin Antibiotics Antineoplastic Organic Chemistry Glutathione DNA chemistry Thiol Molecular Medicine medicine.drug |
| Zdroj: | Bioorganicmedicinal chemistry. 18(5) |
| ISSN: | 1464-3391 |
| Popis: | Enediyne anticancer drugs belong to one of the most potent category in inducing DNA damage. We report 85 ± 5% inhibition on activity of neocarzinostatin by salt. As high sodium ion concentration is a known tumor cell feature, we explored the dynamic mechanism of inhibition. Using various analytical tools, we examined parameters involved in the four consecutive steps of the drug action, namely, drug releasing from carrier protein, drug–DNA binding, drug activating, and DNA damaging. Neither protein stability, nor drug release rate, was altered by salt. The salt inhibition level was similar in between the protein-bound and unbound enediyne chromophore. Salt did not quench the thiol-induced drug activation. The inhibition was independent of DNA lesion types and irrelevant with thiol structures. Collectively, no salt interaction was found in the releasing, activating, and DNA damaging step of the drug action. However, binding with DNA decreased linearly with salt and corresponded well with the salt-induced inhibition on the drug activity. Salt interference on the affinity of DNA binding was the main and sole cause of the severe salt inhibition. The inhibition factor should be carefully considered for all agents with similar DNA binding mode. |
| Databáze: | OpenAIRE |
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