In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1939-1939
Abstract:
Triapine, which is currently tested in a clinical phase III trial, is the best-studied thiosemicarbazone (TSC) for anticancer therapy. With regard to the mode of action, anticancer activity of TSCs is frequently linked to their ability to chelate essential metal ions such as copper and iron. As Triapine monotherapy showed promising results mainly against hematological diseases, novel TSC derivatives have been developed and clinically investigated for their activity against solid tumors. These novel TSCs belong to a subclass with enhanced anticancer activity in vitro and in vivo which were recently discovered to induce paraptosis, a form of programmed but caspase-independent cell death. As these TSCs are characterized by a up to 1000-fold higher activity in cell culture compared to Triapine, the aim of this study was to elucidate the mechanism of action as well as the underlying structural and chemical requirements of these effects. For this purpose, a panel of structurally related Triapine derivatives was examined for anticancer activity (as metal-free ligand and copper(II) complex), paraptosis-inducing potential as well as solution stability and redox properties of their copper(II) complexes. Correlation studies between these chemical and biological properties revealed that the increased anticancer activity and paraptosis-inducing potential of the nanomolar active TSCs is related to a higher copper(II) complex solution stability and slower reduction rate. Unexpectedly, the TSCs with lower activity produced higher superoxide levels in a cell-free setting. This paradox could be explained by their lower copper(II) complex stability and increased readiness to be reduced, which resulted in a fast reduction of intracellular complexes and release of the metal-free ligand. Although this process resulted in the generation of superoxide, cell damage seemed to be prevented by rapid upregulation of the superoxide dismutase (in vitro and in vivo). In contrast, the copper complexes of the highly active TSCs are stable enough to reach intracellular targets such as the ER-resident protein disulfide isomerase, whose inhibition is crucial for paraptosis induction by TSCs. In conclusion, copper complex stability is a crucial parameter of TSC activity, influencing the (intracellular) formation or dissociation of copper complexes. This intracellular stability of complexes, affects their mechanism of action as well as cell death induction. Overall, this study points out the importance of the redox parameters in order to understand and predict the TSC anticancer activity as well as their mechanism of action and, thereby, will pave the way for the development of improved anticancer agents. Citation Format: Sonja Hager, Veronika F. Pape, Vivien Pósa, Bianca Montsch, Lukas Uhlik, Gergely Szakàcs, Szilárd Tóth, Nikolett Jabronka, Bernhard K. Keppler, Walter Berger, Christian R. Kowol, Éva A. Enyedy, Petra Heffeter. Improved activity and paraptosis-induction of anticancer thiosemicarbazones requires high copper(II) complex stability and slow reduction kinetics [abstract] . In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1939.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2020-1939
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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