Degradation of topoisomerase I induced by topoisomerase I inhibitors is dependent on inhibitor structure but independent of cell death.
DNA topoisomerase I (top I) is the target of the antitumor drug camptothecin (CPT) and its analogs. CPT induces dose- and time-dependent degradation of top I. Degradation of top I also occurs in a CPT-resistant cell line and, therefore, is not a consequence of cell death. Top I degradation is preceded by the appearance of a high molecular weight ladder of top I immunoreactivity and can be blocked by specific inhibitors of the proteasome. We compared the effects of five top I poisons [CPT, topotecan, 6-N-formylamino-12,13-dihydro-1, 11-dihydroxy-13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3, 4-c]carbazole-5,7(6H)-dione (NB506), camptothecin-(para)-4beta-amino-4'-O-demethyl Epipodophyllotoxin (W1), and camptothecin-(ortho)-4beta-amino-4'-O-demethyl Epipodophyllotoxin (W2)] on cleavable complex formation and top I degradation. Although all five drugs induced cleavable complex formation, two of the drugs, NB506 and W1 did not induce top I degradation.
Fu
Q
Q
Yale University, School of Medicine, Department of Pharmacology, New Haven, Connecticut 06520, USA.
Kim
S W
SW
Chen
H X
HX
Grill
S
S
Cheng
Y C
YC
D000328:Adult; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007624:KB Cells; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D013329:Structure-Activity Relationship; D013997:Time Factors; D059004:Topoisomerase I Inhibitors
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D059004:Topoisomerase I Inhibitors; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin