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Selective Cytotoxicity of Rhodium Metalloinsertors in Mismatch Repair-Deficient Cells

Ernst, Russell J. and Komor, Alexis C. and Barton, Jacqueline K. (2011) Selective Cytotoxicity of Rhodium Metalloinsertors in Mismatch Repair-Deficient Cells. Biochemistry, 50 (50). pp. 10919-10928. ISSN 0006-2960. PMCID PMC3364161. doi:10.1021/bi2015822. https://resolver.caltech.edu/CaltechAUTHORS:20120124-084500760

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Abstract

Mismatches in DNA occur naturally during replication and as a result of endogenous DNA damaging agents, but the mismatch repair (MMR) pathway acts to correct mismatches before subsequent rounds of replication. Rhodium metalloinsertors bind to DNA mismatches with high affinity and specificity and represent a promising strategy to target mismatches in cells. Here we examine the biological fate of rhodium metalloinsertors bearing dipyridylamine ancillary ligands in cells deficient in MMR versus those that are MMR-proficient. These complexes are shown to exhibit accelerated cellular uptake which permits the observation of various cellular responses, including disruption of the cell cycle, monitored by flow cytometry assays, and induction of necrosis, monitored by dye exclusion and caspase inhibition assays, that occur preferentially in the MMR-deficient cell line. These cellular responses provide insight into the mechanisms underlying the selective activity of this novel class of targeted anticancer agents.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/bi2015822 DOIArticle
http://pubs.acs.org/doi/abs/10.1021/bi2015822PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364161/PubMed CentralArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2011 American Chemical Society. Received: October 14, 2011. Publication Date (Web): November 21, 2011. Financial support for this work from the NIH (GM33309) is gratefully acknowledged. We also thank Amgen, the Parsons foundation, and the ARCS foundation for fellowship support to R.J.E. as well as NSF for a predoctoral fellowship to A.C.K. We thank also R. Diamond and the Beckman Institute for expertise in flow cytometry.
Funders:
Funding AgencyGrant Number
NIHGM33309
AmgenUNSPECIFIED
Ralph M. Parsons FoundationUNSPECIFIED
ARCS FoundationUNSPECIFIED
NSF Predoctoral FellowshipUNSPECIFIED
Issue or Number:50
PubMed Central ID:PMC3364161
DOI:10.1021/bi2015822
Record Number:CaltechAUTHORS:20120124-084500760
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120124-084500760
Official Citation:Selective Cytotoxicity of Rhodium Metalloinsertors in Mismatch Repair-Deficient Cells Russell J. Ernst, Alexis C. Komor, and Jacqueline K. Barton Biochemistry 2011 50 (50), 10919-10928
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:28930
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:24 Jan 2012 16:58
Last Modified:09 Nov 2021 17:02

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