Selective cytotoxicity of rhodium metalloinsertors in mismatch repair-deficient cells.

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.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Ernst RJ,Komor AC,Barton JK

doi

10.1021/bi2015822

subject

Has Abstract

pub_date

2011-12-20 00:00:00

pages

10919-28

issue

50

eissn

0006-2960

issn

1520-4995

journal_volume

50

pub_type

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