The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

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. © 2018, The Author(s)

EFFECTS OF METAL(III) COORDINATION ON BIOLOGICAL ACTIVITY OF 2,2'-BIPYRIDYL-6-CARBOTHIOAMIDE (BPYTA), A POTENT R2 RIBONUCLEOTIDE REDUCTASE INHIBITOR

Investigations from our laboratory have led to the development of 2,2'-bipyridyl-6-carbothioamide (BPYTA), that demonstrated a powerful cytotoxicity for rodent and human tumoral cell lines and for peripheral blasts from patients suffering from acute leukemia.1 The BPYTA cytotoxic effect is mainly due to the inhibition of ribonucleotide reductase (RR), the enzyme responsible for reductive conversion of ribo- to deoxyribonucleotides that has long been regarded as an important target for therapies aiming to control pathologies that depend strongly on DNA replication. BPYTA is characterized by chelating properties because of the N*-N*-S* tridentate coordination system similar to that of α-(N)-heterocyclic carboxaldehyde thiosemicarbazones, whose metal complexes have been extensively investigated. However, the properties of BPYTA-complexes and thiosemicarbazone-complexes are not identical. Among the transition-metal(II) complexes with BPYTA, the iron chelate [BPYTA-Fe(II), molar ratio 2:1], is the active form of the ligand which destroys the tyrosyl radical of RR small subunit R2, while other transition-metal complexes resulted in significant differences in biochemical effects of the ligand and, perhaps, also for its mechanism of action.2 In the present study we report on the effects of metal(III) coordination on the pharmacological properties of BPYTA. In particular, new complexes with gallium(III) and iron(III) with the general formula [M(L)2]+ have been prepared and investigated for their biological activity. Moreover, a novel improved and inexpensive synthesis of BPYTA has been developed. References 1-NOCENTINI, G., et al., 1993. 2,2'-Bipyridyl-6-carbothioamide and its ferrous complex: their in vitro antitumoral activity related to the inhibition of ribonucleotide reductase R2 subunit. Cancer Research, 53, 19-26. 2-FRANCHETTI, P., et al., 1988. Metal(II) complexes of 2,2'-bipyridyl-6-carbothioamide as antitumor and antifungal agents. European Journal of Medicinal Chemistry, 23, 301-305

Mechanisms underlying reductant-induced reactive oxygen species formation by anticancer copper(II) compounds

Intracellular generation of reactive oxygen species (ROS) via thiol-mediated reduction of copper(II) to copper(I) has been assumed as the major mechanism underlying the anticancer activity of copper(II) complexes. The aim of this study was to compare the anticancer potential of copper(II) complexes of Triapine (3-amino- pyridine-2-carboxaldehyde thiosemicarbazone; currently in phase II clinical trials) and its terminally dimethylated derivative with that of 2-formylpyridine thiosemicarbazone and that of 2,2' -bipyridyl-6-carbothioamide. Experiments on generation of oxidative stress and the influence of biologically relevant reductants (glutathione, ascorbic acid) on the anticancer activity of the copper complexes revealed that reductant-dependent redox cycling occurred mainly outside the cells, leading to generation and dismutation of superoxide radicals resulting in cytotoxic amounts of H2O2. However, without extracellular reductants only weak intracellular ROS generation was observed at IC50 levels, suggesting that cellular thiols are not involved in copper- complex-induced oxidative stress. Taken together, thiol- induced intracellular ROS generation might contribute to the anticancer activity of copper thiosemicarbazone complexes but is not the determining factor

Biological activity of two isomeric N-heteroaromatic selenosemicarbazones and their metal complexes

New square-planar Pd(II) and Pt(II) complexes with 8-quinolinecarboxaldehyde selenosemicarbazone have been synthesized and characterized by use of elemental analysis, molar conductivity measurements, and IR and NMR spectroscopy. The cytotoxic activity of the ligand, new Pt(II) and Pd(II) compounds, and previously synthesized Pd(II), Pt(II), Cd(II), and Ni(II) complexes with the analogous ligand, 2-quinolinecarboxaldehyde selenosemicarbazone, was tested against two human cancer cell lines: lung carcinoma (H460) and glioma (U251). The potential of these compounds to induce perturbations of the H460 cell cycle was also evaluated. These substances had an excellent radical-scavenging effect against ABTS radical cations. The best antimicrobial activity, among two yeasts and eight bacterial strains tested, was against Bacillus cereus