engleski

Development of potential anti-cancer drugs: diazenes and derivatives

In order to improve the effectiveness of cancer treatment, new anticancer drugs have been synthesised that may reduce the activity of some of the essential molecules for cellular homeostasis. Glutathione (GSH), a ubiquitous thiol containing tripeptide, is recognized to be such target. Its role in the cellular defence due to detoxification of xenobiotics, and protection against oxidative stress has been recognised many years ago and has been studied for years. Recently, however, evidence has emerged that suggest the essential role of GSH in the activation or inhibition of proteins fundamental to cell survival, especially in the control of apoptotic cell death. These findings focus the research to the discovery of drugs that may be GSH targeted, thus inhibiting the growth of tumour cells. We have synthesised very recently new compounds, diazenes, as selective oxidants for a mild transformation of various thiols to the corresponding disulfides (1). Diazenes easily oxidize cysteamine, thiosalicylic acid derivatives, dithiothreitol and others in methanol at room temperature. Under quasi-physiological conditions they interact also with GSH (1). That stimulated us to examine their cytotoxic activity against several tumour cell lines in vitro. This presentation is the review of five years research collaboration between Slovenian group that synthesises new compounds, diazenes and their derivatives (team leader S. Polanc), and Croatian group that examine the cytotoxicity of these compounds and the causes of cytotocixity (team leader M. Osmak). So far we have examined about sixty new compaunds. We have found that: a) several diazenes inhibited the growth of different tumour cell lines (glioblastoma, cervical, laryngeal and mammary carcinoma cells) (2-8) ; b) some of them reduced the survival of drug-resistant cells as well (the ability of malignant cells to develop resistance to anticancer drugs is the major obstacle to the ultimate success in cancer therapy) (2, 5-7) ; c) for some of these compounds the target was the intracellular glutathione (3, 6) ; and d) several diazenes were able to revert the resistance of tumour cells to cisplatin and /or vincristine (3, 4). For the most promising new compound, the type of induced cell death was examined as well. The most important findings of this research will be presented in more details. 1. Košmrlj J, Kočevar M, Polanc S, J Chem Soc Perkin Trans 1, 3917– 3919, 1998. 2. Osmak M et al., Anti-Cancer Drugs, 10: 853-859, 1999. 3. Osmak M et al., Neoplasma, 46: 201-206, 1999. 4. Osmak et al., M., Neoplasma, 47:390-395, 2000. 5. Moskatelo D et al., Chemotherapy, 48:36-41, 2002. 6. Moskatelo Det al., Pharmacol. Toxicol., 91: 258-263, 2002. 7. Čimbora T et al., Toxicol. in Vitro, 17: 159-164, 2003. 8. Čimbora-Zovko T et al., Drug Development Research, 2004.

diazenes; drug-resistance; anti-cancer drugs; glutathione

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