Anthracenedione-methionine conjugates are novel topoisomerase II-targeting anticancer agents with favorable drug resistance profiles

作者：Lee Chieh Hua; Hsieh Mei Yi; Hsin Ling Wei; Chen Hsiang Chin; Lo Su Chi; Fan Jia Rong; Chen Wan Ru; Chen Hung Wei; Chan Nei Li; Li Tsai Kun^*

来源：Biochemical Pharmacology, 2012, 83(9): 1208-1216.

DOI：10.1016/j.bcp.2012.01.025

• Topoisomerase
• Anthracenedione
• Mitoxantrone
• Cleavable complex
• Multi-drug resistance

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-aminoethylamino) (M) under barX- and (A) under barT-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 (hTOP2 alpha and 2 beta) 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 hTOP2 alpha proteins and the formation of hTOP2 alpha/beta cc 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.

• 出版日期2012-5-1