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Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization

Komor, Alexis C. and Schneider, Curtis J. and Weidmann, Alyson G. and Barton, Jacqueline K. (2012) Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization. Journal of the American Chemical Society, 134 (46). pp. 19223-19233. ISSN 0002-7863. PMCID PMC3740518. doi:10.1021/ja3090687. https://resolver.caltech.edu/CaltechAUTHORS:20130111-105340383

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ja3090687DOIArticle
http://pubs.acs.org/doi/abs/10.1021/ja3090687PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740518/PubMed CentralArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 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.
Funders:
Funding AgencyGrant Number
NIHGM03339
NSF Graduate Research FellowshipUNSPECIFIED
American Cancer Society118832-PF-10-017-01-CDD
Issue or Number:46
PubMed Central ID:PMC3740518
DOI:10.1021/ja3090687
Record Number:CaltechAUTHORS:20130111-105340383
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130111-105340383
Official Citation:Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization Alexis C. Komor, Curtis J. Schneider, Alyson G. Weidmann, and Jacqueline K. Barton Journal of the American Chemical Society 2012 134 (46), 19223-19233
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:36320
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:11 Jan 2013 22:07
Last Modified:09 Nov 2021 23:21

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