Cellular Target of a Rhodium Metalloinsertor is the DNA Base Pair Mismatch

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Genetics

Background:

• Defects in DNA mismatch repair (MMR) are prevalent in various cancers, particularly colorectal cancer.
• Current mismatch-targeted therapeutics and diagnostic tools for MMR-deficient cancers are limited.

Purpose of the Study:

• To investigate the cytotoxic properties of the rhodium metalloinsertor [Rh(phen)(chrysi)(PPO)]^2+ (RhPPO) in colorectal cancer cell lines.
• To evaluate RhPPO as a potential anticancer agent and RhCy3 as a diagnostic probe for MMR-deficient cancers.

Main Methods:

• Cytotoxicity assays were performed on 27 diverse colorectal cancer cell lines using RhPPO.
• A fluorescent metalloinsertor, RhCy3, was used to visualize the cellular target of RhPPO and assess MMR-deficiency.
• Correlated RhCy3 fluorescence with RhPPO cytotoxicity across cell lines.

Main Results:

• RhPPO demonstrated significantly higher potency (average five times) than cisplatin against colorectal cancer cell lines.
• The cellular target of RhPPO was identified as the DNA mismatch, distinct from cisplatin's mechanism.
• RhCy3 fluorescence directly correlated with RhPPO's cytotoxicity, serving as a direct indicator of MMR-deficiency.

Conclusions:

• RhPPO is a potent anticancer agent effective against MMR-deficient colorectal cancers.
• RhCy3 serves as a direct diagnostic probe for identifying MMR-deficient cancers.
• RhPPO and RhCy3 represent promising tools for targeted cancer therapy and diagnostics in MMR-deficient malignancies.