Insight into the strong inhibitory action of salt on activity of neocarzinostatin.
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.
Department of Chemistry, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung, Taiwan 40227, ROC. chdhchin@dragon.nchu.edu.tw
Der-Hang
DH
Chin
Huang-Hsien
HH
Li
Christopher G
CG
Sudhahar
Pei-Yin
PY
Tsai
D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D004247:DNA / Q000737:chemistry; D012965:Sodium Chloride / Q000737:chemistry* / Q000378:metabolism; D009353:Zinostatin / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D012965:Sodium Chloride; D004247:DNA; D009353:Zinostatin