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.