Establishment and characterization of 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103)-resistant cell lines

6-[[2- (Dimethylamino)ethyl]amino]-3-hydroxy-7H [2,1-c]quinolin-7-one dihydrochloride (TAS-103) is a novel anticancer agent that was developed to target both topoisomerase (Topo) I and Topo II, To elucidate its mechanism of action, we have established and characterized TAS-103-resistant cells, derived from mouse leukemia (P388), human colon cancer (DLD-1), and human lung adenocarcinoma (A549) cell lines, by exposure to stepwisely increasing concentrations of TAS-103 in the culture medium. P388/TAS cells showed only cross-resistance to VP-16 and adriamycin (ADR), The Topo II activity in these cells was decreased to below one-fourth of that in the parental cells, while the Topo I activity remained unchanged, DLD/TAS cells appeared to be cross-resistant to VP-16, ADR, camptothecin (CPT), SN-38 and vincristine (VCR), The enzymatic activities of both Topo I and Topo II in these cells were decreased to one-fourth of that observed in the parental cells. Furthermore, the decreased activities were accompanied by lower expression at the mRNA and protein levels, A549/TAS cells acquired cross-resistance to VP-16, ADR and VCR, though the Topo activities were virtually unchanged, In this cell line, the intracellular accumulation of TAS-103 was significantly decreased and the expression of multidrug resistance associated protein (MRP) was elevated when compared with the parental cells. The results indicate that the affected activities of Topo I and/or Topo II, and in some instances decreased accumulation of TAS-103, are associated with the development of resistance to TAS-103, although the main mechanism of resistance to TAS-103 varied among cell lines.