CaltechAUTHORS
  A Caltech Library Service

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

Nano, Adela and Bailis, Julie M. and Mariano, Natalie F. and Pham, Elizabeth D. and Threatt, Stephanie D. and Barton, Jacqueline K. (2020) Cell-Selective Cytotoxicity of a Fluorescent Rhodium Metalloinsertor Conjugate Results from Irreversible DNA Damage at Base Pair Mismatches. Biochemistry, 59 (5). pp. 717-726. ISSN 0006-2960. https://resolver.caltech.edu/CaltechAUTHORS:20200122-124618192

[img] PDF - Accepted Version
See Usage Policy.

698Kb
[img] PDF (All of the characterization spectra (i.e., NMR, MS, UV–vis, and HPLC) and additional data on RhPPO-Cy3 cellular cytotoxicity) - Supplemental Material
See Usage Policy.

1252Kb

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20200122-124618192

Abstract

Up to 20% of solid tumors are characterized by DNA mismatch repair (MMR) deficiency and microsatellite instability that confer resistance to standard of care chemotherapy. MMR-deficient cancers have an increased mutation rate, and DNA mismatches accumulate as part of these cancers. 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 occur at or near DNA mismatch sites. RhPPO-Cy3 foci persist over time, despite initial processing of the lesion and recruitment of repair proteins, consistent with the idea that the complex binding to a mismatch prevents repair. RhPPO-Cy3 binding does not lead to activation of p53 and the apoptotic pathway. Together, these findings support the idea that RhPPO-Cy3 binding leads to irreversible DNA damage at DNA mismatches that enables selective cytotoxicity to MMR-deficient cells.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acs.biochem.9b01037DOIArticle
ORCID:
AuthorORCID
Nano, Adela0000-0002-1984-5770
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2020 American Chemical Society. Received: November 25, 2019; Revised: January 21, 2020; Published: January 22, 2020. The authors are grateful to the Beckman Laser Resources Center for its support. The authors thank Christopher Hale (Amgen) for technical assistance with image analysis. Author Contributions: A.N. and J.M.B. contributed equally to this work. This work was supported by funding from Amgen and from the Moore Foundation. The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
AmgenUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Issue or Number:5
Record Number:CaltechAUTHORS:20200122-124618192
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200122-124618192
Official Citation:Cell-Selective Cytotoxicity of a Fluorescent Rhodium Metalloinsertor Conjugate Results from Irreversible DNA Damage at Base Pair Mismatches. Adela Nano, Julie M. Bailis, Natalie F. Mariano, Elizabeth D. Pham, Stephanie D. Threatt, and Jacqueline K. Barton. Biochemistry 2020 59 (5), 717-726; DOI: 10.1021/acs.biochem.9b01037
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100839
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:22 Jan 2020 23:21
Last Modified:11 Feb 2020 23:19

Repository Staff Only: item control page