Cell-Selective Cytotoxicity of a Fluorescent Rhodium Metalloinsertor Conjugate Results from Irreversible DNA Damage at Base Pair Mismatches

Up to twenty percent of solid tumors are characterized by DNA mismatch repair (MMR) deficiency and microsatellite instability (MSI) that confer resistance to standard of care chemotherapy. MMR-deficient cancers have an increased mutation rate and accumulate DNA mismatches. We previously described a class of compounds, rhodium metalloinsertors, that bind DNA mismatches with high specificity and selectivity and have potential as targeted therapy. [Rh(chrysi)(phen)(PPO)]2+ (RhPPO) is the most potent, selective compound in this class and acts by targeting DNA mismatches, resulting in preferential cytotoxicity to MMR-deficient cancers. To explore further the cellular mechanism of action of RhPPO, we conjugated the metal complex to a fluorescent probe, cyanine 3 (Cy3). RhPPO-Cy3 binds DNA mismatches and retains the selectivity and potent cytotoxic activity of RhPPO for MMR-deficient cell lines. RhPPO-Cy3 forms discrete foci in the cell nucleus that overlap with sites of DNA damage, suggesting that the lesions o...