Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization
Deficiencies in the mismatch repair (MMR) pathway are associated with several types of cancers, as well as resistance to commonly used chemotherapeutics. Rhodium metalloinsertors have been found to bind DNA mismatches with high affinity and specificity in vitro, and also exhibit cell-selective cytotoxicity, targeting MMR-deficient cells over MMR-proficient cells. Ten distinct metalloinsertors with varying lipophilicities have been synthesized and their mismatch binding affinities and biological activities determined. Although DNA photocleavage experiments demonstrate that their binding affinities are quite similar, their cell-selective antiproliferative and cytotoxic activities vary significantly. Inductively coupled plasma mass spectrometry (ICP-MS) experiments have uncovered a relationship between the subcellular distribution of these metalloinsertors and their biological activities. Specifically, we find that all of our metalloinsertors localize in the nucleus at sufficient concentrations for binding to DNA mismatches. However, the metalloinsertors with high rhodium localization in the mitochondria show toxicity that is not selective for MMR-deficient cells, whereas metalloinsertors with less mitochondrial rhodium show activity that is highly selective for MMR-deficient versus proficient cells. This work supports the notion that specific targeting of the metalloinsertors to nuclear DNA gives rise to their cell-selective cytotoxic and antiproliferative activities. The selectivity in cellular targeting depends upon binding to mismatches in genomic DNA.
© 2012 American Chemical Society. Published In Issue November 21, 2012; Article ASAP: November 08, 2012; Received: September 12, 2012. Financial support for this work from the NIH (GM03339) is gratefully acknowledged. We also thank the National Science Foundation for a Graduate Research Fellowship to A.C.K. and the American Cancer Society for a Postdoctoral Fellowship to C.J.S. (118832-PF-10-017-01-CDD). This project benefitted from the use of instrumentation made available by the Caltech Environmental Analysis Center.
Published - ja3090687.pdf
Accepted Version - nihms442195.pdf
Supplemental Material - ja3090687_si_001.pdf