Multiple mechanisms for cytotoxicity induced by copper(II) complexes of 2‐acetylpyrazine‐N‐substituted thiosemicarbazones

Abstract

The purpose of this study was to evaluate the mechanism by which 2-acetylpyrazine-4 N-substituted thiosemicarbazone copper II complexes mediate their cytotoxicity. These compounds were shown to be cytotoxic to a variety of human and rodent tumors in cell culture and are potent cytocidal agents as determined by dilute agar colony assays. They demonstrated the ability to inhibit several enzymes in vitro including DNA topoisomerase II activity. The data presented suggest that cytotoxicity may be mediated by the cumulative effect of several enzymes being inhibited by the agents. Copyright #

The Cytotoxicity of Symmetrical and Unsymmetrical Bis(thiosemicarbazones) and Their Metal Complexes in Murine and Human Tumor Cells

“…In fact the resulting ED 50 values for the nickel bis(thiosemicarbazones) were essentially the same as the previously reported nickel thiosemicarbazones [3] . The cytotoxic values of the copper(II) complexes, 10-29, were very similar to the uncomplexed bis(thiosemicarbazones), 1-3, as well as the copper(II) complexes of heterocyclic thiosemicarbazones [4][5][6] in blocking the growth of suspended tumor cell growth.…”

“…There was no significant difference in the ED 50 values in these tumor lines between the nickel(II) bis(thiosemicarbazones) and the nickel(II) heterocyclic thiosemicarbazones [3] . The copper(II) bis(thiosemicarbazones) were not as active as the copper(II) complexes of heterocyclic thiosemicarbazones [1][2][3][4][5][6] , although there are selected bis(thiosemicarbazones) which did show comparable activity in KB nasopharynx and colon SW480 colon growth. The copper complexes of bis(thiosemicarbazones) did demonstrate good activity against ovary 1-A9 carcinoma growth; there are few drugs which are effective in reducing its growth of this tumor cell line.…”

“…Previously, a mode of action study was conducted with the nickel(II) and copper(II) complexes of heterocyclic thiosemicarbazones in murine L1210 lymphoid leukemia cell line [1][2][3][4][5][6] . Presently, the bis(thiosemicarbazones)copper complexes were examined in human HL-60 leukemia cells.…”

“…Heterocyclic N(4)-substituted thiosemicarbazones, N-(2)pyridyl-N′-arylthioureas, and 2-substituted pyridine N-oxides and their copper(II) complexes have been shown to be potent antineoplastic agents, and cytotoxicity has been demonstrated against the growth of a number of murine and human tumor cells [1][2][3][4][5][6][7] . The 2-acetylpyridine N(4)-substituted thiosemicarbazones have demonstrated significant activity in the NCI screens for non-small cell lung cancer, breast cancer, and prostate cancer and leukemias [2].…”

“…The 2-acetylpyridine N(4)-substituted thiosemicarbazones have demonstrated significant activity in the NCI screens for non-small cell lung cancer, breast cancer, and prostate cancer and leukemias [2]. Mode of action studies in L1210 lymphoid leukemia cells have demonstrated that these agents inhibit DNA and RNA syntheses at the enzymatic sites of IMP dehydrogenase, DNA polymerase α, ribonucleotide reductase, dihydrofolate reductase, nucleoside kinases, DNA topoisomerase II with DNA strand scission without DNA protein linked breaks [1][2][3][4][5][6] . The 2-formyl-, 2-acetyl-, and 2-benzoylpyridine N(4)-substituted thiosemicarbazones and their copper complexes demonstrated potent cytotoxic activity against the growth of human MCK-7 breast effusion, lung A549, and lung MB-9812, bone osteosarcoma Saos-2, and clear cell Caki renal tumor [7] .…”