Copper Ion Attenuated the Antiproliferative Activity of Di-2-pyridylhydrazone Dithiocarbamate Derivative; However, There Was a Lack of Correlation between ROS Generation and Antiproliferative Activity

Abstract

Abstract:The use of chelators for cancer treatment has been an alternative option. Dithiocarbamates have recently attracted considerable attention owning to their diverse biological activities; thus, the preparation of new dithiocarbamate derivatives with improved antitumor activity and selectivity as well as probing the underlying molecular mechanism are required. In this study, di-2-pyridylhydrazone dithiocarbamate S-propionic acid (DpdtpA) and its copper complex were prepared and characterized, and its antiproliferative activity was evaluated. The proliferation inhibition assay showed that DpdtpA exhibited excellent antiproliferative effect in hepatocellular carcinoma (IC 50 = 1.3 ± 0.3 µM for HepG2, and 2.5 ± 0.6 µM for Bel-7402). However, in the presence of copper ion, the antiproliferative activity of DpdtpA was dramatically attenuated (20-30 fold) owing to the formation of copper chelate. A preliminarily mechanistic study revealed that reactive oxygen species (ROS) generation mediated the antiproliferative activity of DpdtpA, and accordingly induced apoptosis, DNA cleavage, and autophagy. Surprisingly, the cytotoxicity of DpdtpA copper complex (DpdtpA-Cu) was also involved in ROS generation; however, a paradoxical relation between cellular ROS level and cytotoxicity was observed. Further investigation indicated that DpdtpA could induce cell cycle arrest at the S phase; however, DpdtpA-Cu lacked this effect, which explained the difference in their antiproliferative activity.

Antiproliferative activity of di-2-pyridylhydrazone dithiocarbamate acetate partly involved in p53 mediated apoptosis and autophagy

“…In the present study, we demonstrated that copper ion significantly attenuated antiproliferative activity of DpdtaA against HepG2 cells (Fig. 2), which was similar to that previously reported for DpdtpA (19). The two dithiocarbamtes (DpdtaA and DpdtpA) have similar structures, only one carbon difference, their antiproliferative effect against HepG2 cells was also similar, but upon chelation of copper, the propionic acid thiol ester showed greater fold decrease than acetate in antiproliferation.…”

“…As shown in Fig. 2A-D, the DpdtaA caused rounded HepG2 cells, but the addition of copper ion significantly attenuated the action, showing an antagonistic effect as we previously reported (19). We speculated that the 'antagonistic effect' might stem from a new species which was confirmed at DpdtaA/Cu =1:1 ratio in composition by spectral titration (data not shown).…”

“…DpdtaA (generated by ACDLabs: 3-[({2-[di(pyridin-2-yl)methylidene] hydrazinyl} carbonothioyl) sulfanyl] acetic acid) was made by three-step reactions as indicated in Fig. 1: the first two steps were as previously described (19). In addition, the final product (DpdtaA) was prepared by reaction of di-2-pyridylhydrazone dithiocarbamate (1 mmol) with 2-bromo acetic acid in absolute ethanol (5 ml), the yellow solid was filtered and washed with ethanol.…”

“…1 was used to generate the DpdtaA. Firstly, hydrazine reacted with carbon disulfide to form hydrazine dithiocarbamate (HdtC, I), then following addition of dipyridineketone, the dipyridylhydrazone dithiocarbamate (DpdtC, II) was made as previously described (19). The DpdtaA (III) was prepared by DpdtC reaction with 2-bromoacetic acid.…”

Copper (I) Nicotinate complex Abrogates Acrylamide Induced Hepatotoxicity in Male Rats: Biochemical and Histological Studies

“…In conclusion our search for this complex might produce more specific anticancer effects is ongoing [71] and copper is an essential element for cell growth many drugs used in clinical practice and has ability and display cytotoxicity [72] . Acryl amide-induced DNA genotoxicity, adduction and mutagenesis Direct interaction of acrylamide with DNA through Michael-type addition reaction is considerably slow [73] , where the interaction of glycidamide with DNA through Michael-type addition is relatively fast as concluded from the semi-empirical MOPAC calculations [74] . The reaction mechanism was suggested to proceed via a preliminary nucleophilic attack of the guanine NH group onto the acrylamide double bond or oxirane ring in glycidamide resulting in the formation of 7-(2-carbamoyl-2-hydroxyethyl)-guanine (N7-GA-Gua), figure 8.…”