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

Kelsey M Boyle1, Adela Nano1, Catherine Day1

  • 1Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, MC 127-72, Pasadena, California, 91125, USA.

Chemistry (Weinheim an Der Bergstrasse, Germany)
|January 8, 2019
PubMed
Summary
This summary is machine-generated.

A new rhodium compound, RhPPO, shows potent anticancer activity against mismatch repair-deficient (MMR-D) colorectal cancers. A fluorescent probe, RhCy3, directly detects MMR-deficiency, enabling targeted cancer diagnostics and therapeutics.

Keywords:
DNA recognitionantitumor agentscancercellular uptakecytotoxicity

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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.