RT Journal Article
SR Electronic
T1 Degradation of Topoisomerase I Induced by Topoisomerase I Inhibitors Is Dependent on Inhibitor Structure but Independent of Cell Death
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 677
OP 683
VO 55
IS 4
A1 Qin Fu
A1 Seung-Whan Kim
A1 Hong-Xin Chen
A1 Susan Grill
A1 Yung-Chi Cheng
YR 1999
UL http://molpharm.aspetjournals.org/content/55/4/677.abstract
AB 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-(β-d-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (NB506), camptothecin-(para)-4β-amino-4′-O-demethyl Epipodophyllotoxin (W1), and camptothecin-(ortho)-4β-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. The American Society for Pharmacology and Experimental Therapeutics