Identification of Compounds Selectively Killing Multidrug-Resistant Cancer Cells

Abstract

There is a great need for the development of novel chemotherapeutic agents that overcome the emergence of multidrug resistance (MDR) in cancer. We catalogued the National Cancer Institute's DTP drug repository in search of compounds showing increased toxicity in MDR cells. By comparing the sensitivity of parental cell lines with MDR derivatives, we identified 22 compounds possessing MDR-selective activity. Analysis of structural congeners led to the identification of 15 additional drugs showing increased toxicity in Pgp-expressing cells. Analysis of MDR-selective compounds led to the formulation of structure activity relationships and pharmacophore models. This data mining coupled with experimental data points to a possible mechanism of action linked to metal chelation. Taken together, the discovery of the MDR-selective compound set shows the robustness of the developing field of MDR-targeting therapy as a new strategy for resolving Pgp-mediated MDR.

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…good agreement with the literature [15,21,40,43,44], the magnitude of MDR selectivity of the N4 para tolyl derivative 1c and the N4 para nitrophenyl derivative 1d is much lower in our test system (compared to reported SR values of 9.2 for 1c and 8.3 for 1d [44]). In fact, 1c is not selective in KB-V1 vs. KB-3-1 and A2780adr vs. A2780 cells.…”

“…that in contrast to the export of toxic substrates, P-gp can directly sensitize MDR cells [15,21,40,43]. Interestingly, the structurally diverse MDR-selective compounds share the ability to chelate metal ions.…”

“…In particular, there is a strong link between the thiosemicarbazone backbone and MDR selective toxicity, as exemplified by several isatin-β-thiosemicarbazones including NSC73306 (1a, Figure 1, upper left panel), NSC658339, NSC716765, NSC716766, NSC716768, NSC716771 and NSC716772 (for structures, see Table S1) [15,21,40,43,44]. In addition to these TSCs the pharmacogenomic approach also identified a benzothiazole (NSC693630, Figure 1, upper middle panel) as a candidate MDRselective agent [15]. The pyrimidinylhydrazone VP035 ( Figure 1, upper right panel) has been reported to show selective toxicity towards MDR cell lines, yet in a P-gp independent manner [13].…”

“…The MDR-selective isatin-β-thiosemicarbazone 1a (NSC73306) is an ONS donor chelator, Dp44mT and Triapine are NNS donor chelators; the benzothiazole NSC693630 is able to bind metal ions via an NNS or NNN coordination mode [15], and the arylhydrazone VP035 is an NNN donor chelator [13,45,46].…”

“…In addition to the reported TSC compounds 1a [15,21,40,43,44], the N4 para tolyl derivative M A N U S C R I P T…”