Abstract
Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me2NNMe2 differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me2NNMe2- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me2NNMe2 (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca2+ and ER thiol redox homeostasis. Our findings indicate that compounds like Me2NNMe2 are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis.
Highlights
Introduction αN-Heterocyclic thiosemicarbazones (TSCs) are a promising class of therapeutics, which have been extensively investigated for their anticancer activity[1,2]
Scale bar: 100 μm. c Increase in cell size of SW480 and HCT-116 cells treated with the indicated concentrations of Triapine and Me2NNMe2 for 48 h action from Triapine[2,12,13]. Their interaction with intracellular copper ions might be important, as intracellularly formed copper complexes have been suggested to be the active metabolites of nanomolar TSCs12–14. In this regard, during our recent studies, we have discovered that treatment with Me2NNMe2 as well as Dp44mT resulted in the formation of perinuclear cytoplasmic vesicles[11] that are characteristic for paraptosis, a recently described new type of programmed cell death[15,16]
Anticancer activity of Triapine and Me2NNMe2 Cytotoxicity and morphological changes induced by Triapine and Me2NNMe2 were investigated in SW480 and HCT-116 cells at different time points (Fig. 1a)
Summary
N-Heterocyclic thiosemicarbazones (TSCs) are a promising class of therapeutics, which have been extensively investigated for their anticancer activity[1,2]. Triapine displayed promising results in clinical phase I and II trials against hematological cancers[3,4,5,6] and has been tested against diverse solid tumors[7,8]. In. Based on promising clinical trials, it is of interest to better elucidate the reasons for the greatly improved anticancer activity of nanomolar TSCs. There are several indications that nanomolar TSCs differ in their mode of Official journal of the Cell Death Differentiation Association. Values given in the graph are the mean ± standard deviation of triplicates from one representative experiment out of three, normalized to the untreated control of the same time-point. IC50 values (μM) ± standard deviations (SD) are given in the table . IC50 values (μM) ± standard deviations (SD) are given in the table . b Morphological changes in SW480 cells induced by 24 and 48 h treatment with the indicated concentrations of Triapine or
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