Anthracenedione-methionine conjugates are novel topoisomerase II-targeting anticancer agents with favorable drug resistance profiles
Journal
Biochemical Pharmacology
Journal Volume
83
Journal Issue
9
Pages
1208-1216
Date Issued
2012
Author(s)
Lee C.-H.
Hsieh M.-Y.
Chen H.-C.
Lo S.-C.
Fan J.-R.
Chen W.-R.
Chen H.-W.
Abstract
Structure-associated drug resistance and DNA-unwinding abilities have greatly limited the clinical usage of anthracenediones, including mitoxantrone (MX) and ametantrone (AT), which intercalate into DNA and induce topoisomerase II (TOP2)-mediated DNA break. We studied a series of 1,4-bis(2-amino-ethylamino) MX- and AT-amino acid conjugates (M/AACs) and showed that abilities in cancer cell killing correlate with the amounts of chromosomal DNA breaks induced by M/AACs. Notably, the 1,4-bis-L/l-methionine-conjugated MAC (L/LMet-MAC) exhibits DNA-breaking, cancer cell-killing and anti-tumor activities rivaling those of MX. Interestingly, l- and d-form Met-M/AACs unwind DNA poorly compared to MX and AT. The roles of the two human TOP2 isozymes (hTOP2α and 2β) in the L/LMet-MAC-induced DNA breakage and cancer cell-killing were suggested by the following observations: (i) M/AAC-induced DNA breakage, cytotoxicity and apoptosis are greatly reduced in various TOP2-deficient conditions; (ii) DNA breaks induced by MACs are highly reversible and effectively antagonized by the TOP2 catalytic inhibitors; (iii) MACs induced differential TOP2-mediated DNA cleavage in vitro using recombinant hTOP2α proteins and the formation of hTOP2α/βcc in the cell culture system. Interestingly, d-aa-conjugated MACs often caused a lower level in hTOP2-mediated DNA breaks and cell-killing than the corresponding l-form ones indicating a steric-specific effect of MACs. Together, our results suggest that both enzyme- and DNA-drug interactions might contribute to TOP2-targeting by M/AACs. Furthermore, Met-MACs are poor substrates for the MDR1 transporter. Therefore, L/LMet-MAC represents a promising class of TOP2-targeting drugs with favorable drug resistance profiles. ? 2012 Elsevier Inc.
SDGs
Other Subjects
ametantrone; anthraquinone; antineoplastic agent; carrier protein; DNA topoisomerase (ATP hydrolysing); gyrase inhibitor; methionine; methionine mitoxantrone ametantrone conjugate; mitoxantrone; multidrug resistance protein 1; unclassified drug; animal experiment; animal model; antineoplastic activity; apoptosis; article; cell killing; complex formation; controlled study; cytotoxicity; DNA cleavage; DNA strand breakage; drug conjugation; drug structure; gene targeting; human; human tissue; IC 50; leukemia; male; mouse; multidrug resistance; nonhuman; priority journal; Animals; Anthraquinones; Antigens, Neoplasm; Antineoplastic Agents; DNA Breaks; DNA Damage; DNA Topoisomerases, Type II; DNA-Binding Proteins; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; Male; Methionine; Mice; Mice, SCID; Mitoxantrone; P-Glycoprotein; Structure-Activity Relationship
Type
journal article