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Rhodium Complexes Targeting DNA Mismatches as a Basis for New Therapeutics in Cancers Deficient in Mismatch Repair

Nano, Adela and Dai, Joanne and Bailis, Julie M. and Barton, Jacqueline K. (2021) Rhodium Complexes Targeting DNA Mismatches as a Basis for New Therapeutics in Cancers Deficient in Mismatch Repair. Biochemistry, 60 (26). pp. 2055-2063. ISSN 0006-2960. doi:10.1021/acs.biochem.1c00302. https://resolver.caltech.edu/CaltechAUTHORS:20210609-150237052

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Abstract

Cancers with microsatellite instability (MSI), which include ≤20% of solid tumors, are characterized by resistance to chemotherapy due to deficiency in the DNA mismatch repair (MMR) pathway. Rhodium metalloinsertors make up a class of compounds that bind DNA mismatches with high specificity and show selective cytotoxicity in MSI cancer cells. We determined that rhodium complexes with an N∧O coordination showed significantly increased cell potency compared with that of N∧N-coordinated compounds, and we identified [Rh(chrysi)(phen)(PPO)]²⁺ (RhPPO) as the most potent, selective compound in this class. Using matched cell lines that are MMR-deficient (HCT116O) and MMR-proficient (HCT116N), we demonstrated that RhPPO preferentially activates the DNA damage response and inhibits DNA replication and cell proliferation in HCT116O cells, leading to cell death by necrosis. Using a fluorescent conjugate of RhPPO, we established that the metalloinsertor localizes to DNA mismatches in the cell nucleus and causes DNA double-strand breaks at or near the mismatch sites. Evaluation of RhPPO across MMR-deficient and MMR-proficient cell lines confirmed the broad potential for RhPPO to target MSI cancers, with cell potency significantly higher than that of platinum complexes used broadly as chemotherapeutics. Moreover, in a mouse xenograft model of MSI cancer, RhPPO shows promising antitumor activity and increased survival. Thus, our studies indicate that RhPPO is a novel DNA-targeted therapy with improved potency and selectivity over standard-of-care platinum-based chemotherapy and, importantly, that DNA mismatches offer a critical new target in the design of chemotherapeutics for MSI cancers.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acs.biochem.1c00302DOIArticle
ORCID:
AuthorORCID
Nano, Adela0000-0002-1984-5770
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2021 American Chemical Society. Received: April 29, 2021; Revised: June 7, 2021; Published: June 11, 2021. The authors are grateful to our many collaborators through the years for their persistence in exploring a completely novel set of metal complexes with a DNA mismatch as the target. This work was funded through Amgen and originally through the National Institutes of Health, for which the authors are grateful. The authors declare the following competing financial interest(s): J.D. and J.M.B. are employees of Amgen, Inc. A.N. and J.K.B. declare no competing financial interests.
Funders:
Funding AgencyGrant Number
AmgenUNSPECIFIED
NIHUNSPECIFIED
Subject Keywords:Cancer, Rhodium, Genetics, Antineoplastic agents, Cells
Issue or Number:26
DOI:10.1021/acs.biochem.1c00302
Record Number:CaltechAUTHORS:20210609-150237052
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210609-150237052
Official Citation:Rhodium Complexes Targeting DNA Mismatches as a Basis for New Therapeutics in Cancers Deficient in Mismatch Repair. Adela Nano, Joanne Dai, Julie M. Bailis, and Jacqueline K. Barton. Biochemistry 2021 60 (26), 2055-2063; DOI: 10.1021/acs.biochem.1c00302
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109455
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:23 Jun 2021 19:43
Last Modified:08 Jul 2021 21:42

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