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

Biochemistry
Adela NanoJacqueline K Barton

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...Continue Reading

References

Aug 15, 1986·Science·J K Barton
Jan 1, 1985·Biochimica Et Biophysica Acta·A L Pinto, S J Lippard
Jan 1, 1996·Annual Review of Biochemistry·P Modrich, R Lahue
Mar 1, 2003·Proceedings of the National Academy of Sciences of the United States of America·Henrik JunickeJacqueline K Barton
Mar 25, 2005·Nature Reviews. Drug Discovery·Dong Wang, Stephen J Lippard
Feb 9, 2006·Chemical Reviews·Ravi R IyerPaul L Modrich
Oct 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Jonathan R HartJacqueline K Barton
Dec 30, 2006·Proceedings of the National Academy of Sciences of the United States of America·Valérie C PierreJacqueline K Barton
Jul 13, 2007·Nature Reviews. Cancer·Lloyd Kelland
Sep 20, 2007·Journal of the American Chemical Society·Christine CordierJacqueline K Barton
Nov 9, 2007·Chemical Communications : Chem Comm·Brian M ZeglisJacqueline K Barton
Jan 30, 2009·Journal of the American Chemical Society·Russell J ErnstJacqueline K Barton
Nov 23, 2011·Biochemistry·Russell J ErnstJacqueline K Barton
Nov 10, 2012·Journal of the American Chemical Society·Alexis C KomorJacqueline K Barton
Feb 21, 2013·Chemical Communications : Chem Comm·Alexis C Komor, Jacqueline K Barton
Sep 26, 2014·Journal of the American Chemical Society·Alexis C Komor, Jacqueline K Barton
Jun 2, 2015·The New England Journal of Medicine·Dung T LeLuis A Diaz
Sep 1, 2015·International Journal of Oncology·Susan Richman
Nov 4, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Thierry AndréAimery de Gramont
Jun 22, 2017·Proceedings of the National Academy of Sciences of the United States of America·Julie M BailisJacqueline K Barton
Nov 15, 2017·Journal of the American Chemical Society·Adela NanoJacqueline K Barton
Jan 23, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Michael J OvermanThierry André
Apr 6, 2018·Journal of the American Chemical Society·Kelsey M Boyle, Jacqueline K Barton
Jan 8, 2019·Chemistry : a European Journal·Kelsey M BoyleJacqueline K Barton
Feb 23, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Leigh MarcusRichard Pazdur
Jul 15, 2020·Proceedings of the National Academy of Sciences of the United States of America·Stephanie D ThreattJacqueline K Barton
Dec 29, 2020·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Romain CohenQian Shi

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Imaging

Imaging techniques, including CT and MR, have become essential to tumor detection, diagnosis, and monitoring. Here is the latest research on cancer imaging.

Related Papers

Proceedings of the National Academy of Sciences of the United States of America
Julie M BailisJacqueline K Barton
Chemistry : a European Journal
Kelsey M BoyleJacqueline K Barton
Proceedings of the National Academy of Sciences of the United States of America
Stephanie D ThreattJacqueline K Barton
Journal of the American Chemical Society
Russell J ErnstJacqueline K Barton
© 2021 Meta ULC. All rights reserved