Characterization of ARC-111 as a Novel Topoisomerase I-Targeting Anticancer Drug

Tsai Kun Li, Peter J. Houghton, Shyamal D. Desai, Parima Daroui, Angela A. Liu, Eszter S. Hars, Alexander L. Ruchelman, Edmond J. LaVoie, Leroy-Fong Liu

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)8400-8407
Number of pages8
JournalCancer Research
Volume63
Issue number23
Publication statusPublished - Dec 1 2003
Externally publishedYes

Fingerprint

Type I DNA Topoisomerase
Drug Delivery Systems
Camptothecin
irinotecan
Antineoplastic Agents
topovale
Neoplasms
Topotecan
U937 Cells
ATP-Binding Cassette Transporters
Wilms Tumor
Ubiquitin
Drug Resistance
Heterografts
Serum Albumin
Colon

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Li, T. K., Houghton, P. J., Desai, S. D., Daroui, P., Liu, A. A., Hars, E. S., ... Liu, L-F. (2003). Characterization of ARC-111 as a Novel Topoisomerase I-Targeting Anticancer Drug. Cancer Research, 63(23), 8400-8407.

Characterization of ARC-111 as a Novel Topoisomerase I-Targeting Anticancer Drug. / 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-Fong.

In: Cancer Research, Vol. 63, No. 23, 01.12.2003, p. 8400-8407.

Research output: Contribution to journalArticle

Li, TK, Houghton, PJ, Desai, SD, Daroui, P, Liu, AA, Hars, ES, Ruchelman, AL, LaVoie, EJ & Liu, L-F 2003, 'Characterization of ARC-111 as a Novel Topoisomerase I-Targeting Anticancer Drug', Cancer Research, vol. 63, no. 23, pp. 8400-8407.
Li TK, Houghton PJ, Desai SD, Daroui P, Liu AA, Hars ES et al. Characterization of ARC-111 as a Novel Topoisomerase I-Targeting Anticancer Drug. Cancer Research. 2003 Dec 1;63(23):8400-8407.
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-Fong. / Characterization of ARC-111 as a Novel Topoisomerase I-Targeting Anticancer Drug. In: Cancer Research. 2003 ; Vol. 63, No. 23. pp. 8400-8407.
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AU - Hars, Eszter S.

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N2 - 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.

AB - 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.

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