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Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug.

Abstract
8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5H-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.
AuthorsTsai-Kun Li, Peter J Houghton, Shyamal D Desai, Parima Daroui, Angela A Liu, Eszter S Hars, Alexander L Ruchelman, Edmond J LaVoie, Leroy F Liu
JournalCancer research (Cancer Res) Vol. 63 Issue 23 Pg. 8400-7 (Dec 01 2003) ISSN: 0008-5472 [Print] United States
PMID14679002 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Naphthyridines
  • Neoplasm Proteins
  • Serum Albumin
  • Topoisomerase I Inhibitors
  • topovale
  • DNA Topoisomerases, Type I
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters (metabolism)
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Cell Division (drug effects)
  • Cell Line, Tumor
  • Colonic Neoplasms (drug therapy, enzymology, pathology)
  • Comet Assay
  • DNA Topoisomerases, Type I (metabolism)
  • Down-Regulation (drug effects)
  • Enzyme Inhibitors (metabolism, pharmacology)
  • Female
  • Humans
  • Mice
  • Mice, SCID
  • Naphthyridines (metabolism, pharmacology)
  • Neoplasm Proteins (metabolism)
  • Protein Binding
  • Serum Albumin (pharmacology)
  • Topoisomerase I Inhibitors
  • Wilms Tumor (drug therapy, enzymology, pathology)
  • Xenograft Model Antitumor Assays

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