Selective Cytotoxicity of Rhodium Metalloinsertors in Mismatch Repair-Deficient Cells
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.
© 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.
Accepted Version - nihms-340111.pdf