Although it is commonly known that metallodrugs target DNA, they may also be deployed to find other effective bio-targets in cancer therapy. A class of small oxindole-copper derivatives has been developed and identified as potential therapeutic agents by Ferreira et al. (J. Inorg. Biochem. 2005, 99, 1433-1440; J. Biol. Chem. 2007, 282, 12010-12021; Carcinogenesis 2009, 30, 1115-1124), in which they were found to induce apoptosis in the human derived neuroblastoma cell line (SH-SY5Y) through mitochondrial pathways, as well as through DNA double cleavage. It was identified that the oxindole-imino [Cu(isaepy)2] acts as a delocalized lipophilic cation, inducing mitochondrial-sited reactive oxygen species production, which leads to dysfunctional mitochondria events and ATP decrease. In addition, [Cu(isaepy)2] has been shown to be involved with AMPK-dependent apoptosis (Biochem. J. 2011, 437, 443�453). We are interested in exploring the potential therapeutic effect of oxindole-copper derivatives on other types of cancer cell lines, such as human sarcoma cell lines MES-SA and MES-SA/DX5. In our effort to further develop potential chemotherapeutic agents, we have tested the cellular viability of different oxindole-containing copper complexes, [Cu(isaepy)2], [Cu(isambz)] and [Cu(isapn)]. This study was also extended to analogous oxindole-containg zinc derivatives. All of them were shown to be citotoxic for both MES-SA and MES-SA/DX5, and their bioactivity was shown to be modulated by the ligand. In the tested series of complexes, [Cu(isaepy)2] so far the most promising species.

Antiproliferative activity of antitumor copper-oxindole agents on human sarcoma cell lines MES-SA and MES-SA/DX5

243rd National Meeting (2012)

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