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In vivo anticancer activity of a rhodium metalloinsertor in the HCT116 xenograft tumor model

Threatt, Stephanie D. and Synold, Timothy W. and Wu, Jun and Barton, Jacqueline K. (2020) In vivo anticancer activity of a rhodium metalloinsertor in the HCT116 xenograft tumor model. Proceedings of the National Academy of Sciences of the United States of America, 117 (30). pp. 17535-17542. ISSN 0027-8424. PMCID PMC7395490. https://resolver.caltech.edu/CaltechAUTHORS:20200714-092121048

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Abstract

Mismatch repair (MMR) deficiencies are a hallmark of various cancers causing accumulation of DNA mutations and mismatches, which often results in chemotherapy resistance. Metalloinsertor complexes, including [Rh(chrysi)(phen)(PPO)]Cl₂ (Rh-PPO), specifically target DNA mismatches and selectively induce cytotoxicity within MMR-deficient cells. Here, we present an in vivo analysis of Rh-PPO, our most potent metalloinsertor. Studies with HCT116 xenograft tumors revealed a 25% reduction in tumor volume and 12% increase in survival with metalloinsertor treatment (1 mg/kg; nine intraperitoneal doses over 20 d). When compared to oxaliplatin, Rh-PPO displays ninefold higher potency at tumor sites. Pharmacokinetic studies revealed rapid absorption of Rh-PPO in plasma with notable accumulation in the liver compared to tumors. Additionally, intratumoral metalloinsertor administration resulted in enhanced anticancer effects, pointing to a need for more selective delivery methods. Overall, these data show that Rh-PPO inhibits xenograft tumor growth, supporting the strategy of using Rh-PPO as a chemotherapeutic targeted to MMR-deficient cancers.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.2006569117DOIArticle
https://www.pnas.org/content/suppl/2020/07/09/2006569117.DCSupplementalPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395490PubMed CentralArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Contributed by Jacqueline K. Barton, May 18, 2020 (sent for review April 8, 2020; reviewed by Jonathan L. Sessler and Brian M. Zeglis). PNAS first published July 13, 2020. We are grateful to the NIH for their long-term support of this research (GM33309 to J.K.B.). We thank Dr. Julie Bailis and Dr. Kelsey Boyle for participating in useful discussions that assisted with the design of this study, as well as Dr. Nathan Dalleska from the Environmental Analysis Center at California Institute of Technology for assistance with the ICP-MS analysis. We also thank Yuming Guo for technical assistance. This work was also performed in the City of Hope Analytical Pharmacology Core Facility supported by the National Cancer Institute under Grant P30CA033572. Author contributions: S.D.T., T.W.S., J.W., and J.K.B. designed research; S.D.T. and T.W.S. performed research; S.D.T., T.W.S., and J.W. analyzed data; and S.D.T. and J.K.B. wrote the paper. Reviewers: J.L.S., The University of Texas at Austin; and B.M.Z., Hunter College. The authors declare no competing interest. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2006569117/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHGM33309
NIHP30CA033572
Subject Keywords:metal–DNA; DNA mismatch; cancer; metal therapeutic
Issue or Number:30
PubMed Central ID:PMC7395490
Record Number:CaltechAUTHORS:20200714-092121048
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200714-092121048
Official Citation:In vivo anticancer activity of a rhodium metalloinsertor in the HCT116 xenograft tumor model. Stephanie D. Threatt, Timothy W. Synold, Jun Wu, Jacqueline K. Barton. Proceedings of the National Academy of Sciences Jul 2020, 117 (30) 17535-17542; DOI: 10.1073/pnas.2006569117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104372
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:14 Jul 2020 16:28
Last Modified:10 Aug 2020 16:09

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