Lipid bilayer-assisted release of an enediyne antibiotic from neocarzinostatin chromoprotein.
The nine-membered enediyne class has drawn extensive interest because of extremely high antitumor potency and intricate interactions with its carrier protein. While the drug-induced DNA cleavage reactions have been mostly elucidated, the critical release-transport process of the labile enediyne molecule in cellular environment remained obscure. Using neocarzinostatin chromoprotein as a model, we demonstrated a lipid bilayer-assisted release mechanism. The in vitro enediyne release rate under aqueous conditions was found to be too slow to account for its efficient DNA cleavage action. Via the presence of lipid bilayers, chaotropic agents, or organic solvents, we found the release was substantially enhanced. The increased rate was linearly dependent on the lipid bilayer concentration and the dielectric value of the binary organic solvent mixtures. While lipid bilayers provided a low surrounding dielectricity to assist in drug release, there were no major conformational changes in the apo and holo forms of the carrier protein. In addition, the lifespan of the released enediyne chromophore was markedly extended through partitioning of the chromophore in the hydrophobic bilayer phase, and the lipid bilayer-stabilized enediyne chromophore significantly enhanced DNA cleavage in vitro. Collectively, we depicted how a lipid bilayer membrane efficiently enhanced dissociation of the enediyne chromophore through a hydrophobic sensing release mechanism and then acted as a protector of the released enediyne molecule until its delivery to the target DNA. The proposed membrane-assisted antibiotic release-transport model might signify a new dimension to our understanding of the modus operandi of the antitumor enediyne drugs.
Hariharan
Parameswaran
P
Department of Chemistry, National Chung Hsing University, Taichung 40227, Taiwan, ROC.
Sudhahar
Christopher Gunasekaran
CG
Chou
Shan-Ho
SH
Chin
Der-Hang
DH
D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism; D053837:DNA Cleavage; D053281:Enediynes / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D013050:Spectrometry, Fluorescence; D009353:Zinostatin / Q000737:chemistry* / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D008051:Lipid Bilayers; D009353:Zinostatin