Keter F.K., Kanyanda S., Lyantagaye S.S.L., Darkwa J., Rees D.J.G., Meyer M.
Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park 2006, South Africa; Department of Biotechnology, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa; Department of Molecular Biology and Biotechnology, University of Dar Es Salaam, P.O. Box 35179, Dar es Salaam, Tanzania
Keter, F.K., Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park 2006, South Africa; Kanyanda, S., Department of Biotechnology, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa; Lyantagaye, S.S.L., Department of Molecular Biology and Biotechnology, University of Dar Es Salaam, P.O. Box 35179, Dar es Salaam, Tanzania; Darkwa, J., Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park 2006, South Africa; Rees, D.J.G., Department of Biotechnology, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa; Meyer, M., Department of Biotechnology, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa
Introduction: Cisplatin (cis-diamminedichloroplatinum) was first identified for its anti-bacterial activity, and was later also shown to be an efficient anticancer agent. However, the therapeutic use of this anticancer drug is somewhat limited by its toxic side effects, which include nephrotoxicity, nausea, and vomiting. Furthermore the development of drug-resistant tumours is commonly observed following therapy with cisplatin. Hence there is a need for improved platinum derived drugs to overcome these limitations. Aims: Apoptosis contributes significantly to the cytotoxic effects of anticancer agents such as cisplatin; therefore in this study the potential anticancer properties of a series of pyrazole palladium(II) and platinum(II) complexes, [(3,5-R 2pz) 2PdCl 2] {R = H (1), R = Me (2)} and [(3,5-R 2pz) 2PtCl 2] {R = H (3), R = Me (4)}, were evaluated by assessment of their pro-apoptotic activity. Methods: The induction of apoptosis was measured in CHO cells by the detection of phosphatidylserine (PS) exposure using the annexin V and APOPercentage™ assays; DNA fragmentation using the Terminal deoxynucleotide transferase dUTP Nick End Labelling (TUNEL) assay; and the detection of activated caspase-3. Results: The platinum complexes were shown to be considerably more active than the palladium complexes, with complex 3 demonstrating the highest level of cytotoxic and pro-apoptotic activity. The LD 50 values for complex 3 and cisplatin were 20 and 70 μM, respectively, demonstrating that the cytotoxic activity for complex 3 was three times higher than for cisplatin. Various human cancer cell lines, including CaSki, HeLa, as well as the p53 mutant Jurkat T cell line were also shown to be susceptible to complex 3. Conclusions: Collectively, this in vitro study provides insights into action of palladium and platinum complexes and demonstrates the potential use of these compounds, and in particular complex 3, in the development of new anticancer agents. © 2008 Springer-Verlag.
antineoplastic agent; caspase 3; cisplatin; dichlorobis(3,5 dimethylpyrazole)palladium; dichlorobis(3,5 dimethylpyrazole)platinum; dichlorobis(pyrazole)palladium; dichlorobis(pyrazole)platinum; lipocortin 5; palladium complex; phosphatidylserine; platinum complex; unclassified drug; animal cell; apoptosis; article; cancer cell culture; controlled study; cytotoxicity; DNA fragmentation; drug screening; enzyme activation; human; human cell; in vitro study; LD 50; nick end labeling; nonhuman; priority journal; Animals; Antineoplastic Agents, Alkylating; Apoptosis; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Drug Evaluation, Preclinical; Hela Cells; Humans; Jurkat Cells; Molecular Structure; Organometallic Compounds; Organoplatinum Compounds