title: 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.
authors: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
authors: Russell J
authors: RJ
authors: Ernst
authors: Alexis C
authors: AC
authors: Komor
authors: Jacqueline K
authors: JK
authors: Barton
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D061945:Caspase Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D053843:DNA Mismatch Repair; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007700:Kinetics; D009336:Necrosis / Q000139:chemically induced; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012238:Rhodium / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C409422:(Rh(bpy)2(chrysi))3+; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D056831:Coordination Complexes; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012238:Rhodium