Anthracenedione-methionine conjugates are novel topoisomerase II-targeting anticancer agents with favorable drug resistance profiles.
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.
Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, No. 1 Sec. 1 Jen-Ai Road, Taipei, Taiwan.
Chieh-Hua
CH
Lee
Mei-Yi
MY
Hsieh
Ling-Wei
LW
Hsin
Hsiang-Chin
HC
Chen
Su-Chi
SC
Lo
Jia-Rong
JR
Fan
Wan-Ru
WR
Chen
Hung-Wei
HW
Chen
Nei-Li
NL
Chan
Tsai-Kun
TK
Li
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D053960:DNA Breaks; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D008715:Methionine / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008942:Mitoxantrone / Q000737:chemistry / Q000494:pharmacology; D000075223:Poly-ADP-Ribose Binding Proteins; D013329:Structure-Activity Relationship
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000880:Anthraquinones; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D008715:Methionine; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618812:Top2a protein, mouse