Characterization of ARC-111 as a Novel Topoisomerase I-Targeting Anticancer Drug
Journal
Cancer Research
Journal Volume
63
Journal Issue
23
Pages
8400-8407
Date Issued
2003
Author(s)
Abstract
8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5 H-dibenzo[c,h][1,6] naphthyridin-6-one (ARC-111, topovale) is a new synthetic antitumor agent. In the current study, we show that ARC-111 is highly potent in scid mice carrying human tumor xenografts. ARC-111 was shown to be as active as camptothecin (CPT)-11 in the HCT-8 colon tumor model, and compared favorably with CPT-11 and topotecan in the SKNEP anaplastic Wilms' tumor model. In tissue culture models, ARC-111 exhibited low nM cytotoxicity against a panel of cancer cells. ARC-111 cytotoxicity as well as ARC-111-induced apoptosis was reduced >100-fold in CPT-resistant topoisomerase I (TOP1)-deficient P388/CPT45 cells as compared with P388 cells. Similarly, ARC-111 cytotoxicity was greatly reduced in CPT-resistant CPT-K5 and U937/CR cells, which express CPT-resistant mutant TOP1, suggesting that the cytotoxic target of ARC-111 is TOP1. Indeed, ARC-111, like CPT, was shown to induce reversible TOP1 cleavage complexes in tumor cells as evidenced by specific reduction of the TOP1 immunoreactive band in a band depletion assay, as well as elevation of small ubiquitin modifier-TOP1 conjugate levels and activation of 26S proteasome-mediated degradation of TOP1. Unlike CPT, ARC-111 is not a substrate for the ATP-binding cassette transporter breast cancer resistance protein. In addition, ARC-111 cytotoxicity was not significantly reduced in the presence of human serum albumin. These results suggest that ARC-111 is a promising new TOP1-targeting antitumor drug with a different drug resistance profile than CPT.
SDGs
Other Subjects
8,9 dimethoxy 5 (2 n,n dimethylaminoethyl) 2,3 methylenedioxy 5h dibenzo[ch][1,6]naphthyridin 6 one; antineoplastic agent; arc 111; breast cancer resistance protein; camptothecin; DNA topoisomerase; irinotecan; serum albumin; topotecan; unclassified drug; animal cell; antineoplastic activity; apoptosis; article; controlled study; cytotoxicity; drug structure; human; human cell; immunoreactivity; mouse; nephroblastoma; nonhuman; priority journal; SCID mouse; tumor xenograft; Animals; Antineoplastic Agents; Apoptosis; ATP-Binding Cassette Transporters; Cell Division; Cell Line, Tumor; Colonic Neoplasms; Comet Assay; DNA Topoisomerases, Type I; Down-Regulation; Enzyme Inhibitors; Female; Humans; Mice; Mice, SCID; Naphthyridines; Neoplasm Proteins; P-Glycoprotein; Protein Binding; Serum Albumin; Wilms Tumor; Xenograft Model Antitumor Assays
Type
journal article