The role of topoisomerases and RNA transcription in the action of the antitumour benzonaphthyridine derivative SN 28049

Abstract

Purpose-SN 28049 (N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide) is a DNA intercalating drug that binds selectively to GC-rich DNA and shows curative activity against the Colon 38 adenocarcinoma in mice. We wished to investigate the roles of topoisomerase (topo) I, topo II and RNA transcription in the action of SN 28049.Methods-We used clonogenic assays to study the cytotoxicity of SN 28049; RNA interference and enzyme assays to examine the role of topo I in SN 28049 action; 3 H uridine incorporation and reporter assays to study its effects on transcription; and RT-PCR to examine its ability to reduce endogenous h-TERT expression. Conclusion-We conclude that SN 28049 has a complex action that may involve poisoning of topo IIα, suppression of topo I and inhibition of gene transcription from promoters with SP-1 sites. These actions may contribute to the promising experimental solid tumour anticancer activity of SN 28049. Results-In

Action of SN 28049, a new DNA binding topoisomerase II-directed antitumour drug: comparison with doxorubicin and etoposide

“…SN 28049 is a DNA binding drug whose dominant action has been shown to be as a poison of topoisomerase IIα [12]. Its effects on NZM3 cells are similar to that of the clinical drug doxorubicin, and in fact SN 28049 has similar potency to this drug.…”

“…The action of SN 28049 was studied in HTETOP human fibrosarcoma cells in which topoisomerase IIα could be down-regulated by addition of tetracycline. SN 28049 induced a 99% reduction of viability in HTETOP wildtype cells but only a 40% reduction when topoisomerase IIα was down-regulated [12], strongly suggesting that topoisomerase IIα is its major enzyme target. Moreover, Jurkat leukaemia cell lines that have developed resistance to doxorubicin or amsacrine [13] have a much reduced topoisomerase II content (Fig.…”

Promising Antitumor Activity of a Novel Quinoline Derivative, TAS-103, against Fresh Clinical Specimens of Eight Types of Tumors Measured by Flow Cytometric DNA Analysis

“…43) Aclarubicin showed the highest ERs and DERs against all of the tumors examined among topoisomerase inhibitors, and these activities are comparable to those of TAS-103 at 5 mg/ml (Tables 3, 4). It is interesting to note that aclarubicin is seemed to be a topo I and topo II inhibitor, 44) like TAS-103. 1) A clinical phase I study of TAS-103 has been carried out against 32 patients; including 16 colorectal, 7 lung, and 5 head and neck.…”

Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

“…[49] Nevertheless, the series exhibited much less dose potency against H460 cells than clinically 50 values against this line in the low nanomolar range. [58,59] Activity of Pyranonaphthoquinone Derivatives against the Catalytic Activity of Human IDO in LLTC-IDO Cells Next we examined the series' ability to inhibit the catalytic activity of IDO-1 in a cellular context by determining the extent to which each compound inhibited the production of the L-tryptophan catabolite, L-kynurenine, in the human IDO-1 overexpressing LLTC-IDO cells. The results showed that there was a dose dependent decrease in L-kynurenine production in the drug treated cells; however the potency of the effect was highly compound dependent (Fig.…”