Cellular Target of a Rhodium Metalloinsertor is the DNA Base Pair Mismatch
Abstract
Defects in DNA mismatch repair (MMR) are commonly found in various cancers, especially in colorectal cancers. Despite the high prevalence of MMR‐deficient cancers, mismatch‐targeted therapeutics are limited and diagnostic tools are indirect. Here, we examine the cytotoxic properties of a rhodium metalloinsertor, [Rh(phen)(chrysi)(PPO)]2+ (RhPPO) in 27 diverse colorectal cancer cell lines. Despite the low frequency of genomic mismatches and the non‐covalent nature of the RhPPO‐DNA lesion, RhPPO is on average five times more potent than cisplatin. Importantly, the biological target and profile for RhPPO differs from that of cisplatin. A fluorescent metalloinsertor, RhCy3, was used to demonstrate that the cellular target of RhPPO is the DNA mismatch. RhCy3 represents a direct probe for MMR‐deficiency and correlates directly with the cytotoxicity of RhPPO across different cell lines. Overall, our studies clearly indicate that RhPPO and RhCy3 are promising anticancer and diagnostic probes for MMR‐deficient cancers, respectively.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 29, 2019
- Source ID
- 10.1002/chem.201900042
Entities
People
- Adela Nano
- Catherine Day
- Jacqueline Barton
- Kelsey M. Boyle
Organizations
- California Institute of Technology
- Gordon and Betty Moore Foundation
- National Institutes of Health
- United States Department of Defense