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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2003-12, Vol.63 (23), p.8400-8407
• Main Authors: LI, Tsai-Kun, HOUGHTON, Peter J, DESAI, Shyamal D, DAROUI, Parima, LIU, Angela A, HARS, Eszter S, RUCHELMAN, Alexander L, LAVOIE, Edmond J, LIU, Leroy F
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Cell Division - drug effects; Cell Line, Tumor; Colonic Neoplasms - drug therapy; Colonic Neoplasms - enzymology; Colonic Neoplasms - pathology; Comet Assay; DNA Topoisomerases, Type I - metabolism; Down-Regulation - drug effects; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Female; Humans; Medical sciences; Mice; Mice, SCID; Naphthyridines - metabolism; Naphthyridines - pharmacology; Neoplasm Proteins - metabolism; Pharmacology. Drug treatments; Protein Binding; Serum Albumin - pharmacology; Topoisomerase I Inhibitors; Tumors; Wilms Tumor - drug therapy; Wilms Tumor - enzymology; Wilms Tumor - pathology; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445

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.