Does cytotoxicity of metallointercalators correlate with cellular uptake or DNA affinity?

Authors

Kimberley J. Davis, University of WollongongFollow
Judith A. Carrall, University of WollongongFollow
Barry Lai, Argonne National Laboratory, Argonne, USA
Janice R. Aldrich-Wright, University of Western Sydney, Nepean
Stephen F. Ralph, University of WollongongFollow
Carolyn T. Dillon, University of WollongongFollow

RIS ID

62411

Publication Details

Davis, K. J., Carrall, J. A., Lai, B., Aldrich-Wright, J. R., Ralph, S. F. & Dillon, C. T. (2012). Does cytotoxicity of metallointercalators correlate with cellular uptake or DNA affinity?. Dalton Transactions, 41 (31), 9417-9426.

Abstract

The cytotoxicity of the metallointercalators, [Pt(5,6-dimethyl-1,10-phenanthroline)(trans-1R,2Rdiaminocyclohexane)] 2+ ([56MERR]) and [Pt(5,6-dimethyl-1,10-phenanthroline)(trans-1S,2Sdiaminocyclohexane)] 2+ ([56MESS]), towards A549 human lung cancer cells was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 value obtained following exposure of A549 cells to [56MESS] for 4 h was approximately three times smaller than that obtained when [56MERR] was administered under the same conditions, indicating that the former complex displayed greater cytotoxicity. Both IC50 values were greater than that obtained after exposure of A549 cells to cisplatin, demonstrating that the latter compound was the most cytotoxic of the three examined. Microprobe synchrotron radiation X-ray fluorescence (SR-XRF) analyses of metallointercalator-treated A549 cells showed that platinum became localised in DNA-rich regions of the nucleus. In contrast, when the same cells were treated with cisplatin the metal became distributed throughout the cell. Determination of the maximum concentration of platinum present inside the cells using graphite furnace atomic absorption spectrophotometry (GFAAS) of platinum-treated cells suggested that there was greater uptake of [56MERR] compared to [56MESS] by the A549 cells, and that platinum uptake did not account for the greater toxicity of [56MESS], as assessed by the MTT assay. Electrospray ionization mass spectrometric (ESI-MS) and circular dichroism (CD) spectroscopic studies of solutions containing either [56MERR] or [56MESS], and a duplex hexadecamer molecule, showed the two metallointercalators displayed very similar affinity towards the nucleic acid. Overall these results indicate that the difference in cytotoxicity of the two platinum metallointercalators is probably the result of variations in their interactions with other cellular components.