https://scholars.lib.ntu.edu.tw/handle/123456789/454016
Title: | Anthracenedione-methionine conjugates are novel topoisomerase II-targeting anticancer agents with favorable drug resistance profiles | Authors: | Lee C.-H. Hsieh M.-Y. LING-WEI HSIN Chen H.-C. Lo S.-C. Fan J.-R. Chen W.-R. Chen H.-W. NEI-LI CHAN TSAI-KUN LI |
Issue Date: | 2012 | Journal Volume: | 83 | Journal Issue: | 9 | Start page/Pages: | 1208-1216 | Source: | Biochemical Pharmacology | 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. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84862809544&doi=10.1016%2fj.bcp.2012.01.025&partnerID=40&md5=f01bb7f882c6abf650552f416b2dfce9 https://scholars.lib.ntu.edu.tw/handle/123456789/454016 |
ISSN: | 0006-2952 | DOI: | 10.1016/j.bcp.2012.01.025 | SDG/Keyword: | 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 |
Appears in Collections: | 生物化學暨分子生物學科研究所 |
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