Attenuation of doxorubicin-induced cardiotoxicity in a human in vitro cardiac model by the induction of the NRF-2 pathway.

Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie
Lauren TomlinsonParveen Sharma

Abstract

Dose-dependent cardiotoxicity is the leading adverse reaction seen in cancer patients treated with doxorubicin. Currently, dexrazoxane is the only approved drug that can partially protect against this toxicity in patients, however, its administration is restricted to those patients receiving a high cumulative dose of anthracyclines. Investigations into the mechanisms of cardiotoxicity and efforts to improve cardioprotective strategies have been hindered by the limited availability of a phenotypically relevant in vitro adult human cardiac model system. Here, we adapted a readily reproducible, functional 3D human multi-cell type cardiac system to emulate patient responses seen with doxorubicin and dexrazoxane. We show that administration of two NRF2 gene inducers namely the semi-synthetic triterpenoid Bardoxolone methyl, and the isothiocyanate sulfurophane, result in cardioprotection against doxorubicin toxicity comparable to dexrazoxane as evidenced by an increase in cell viability and a decrease in the production of reactive oxygen species. We further show a synergistic attenuation of cardiotoxicity when the NRF2 inducers and dexrazoxane are used in tandem. Taken together, our data indicate that the 3D spheroid is a suitable mo...Continue Reading

References

Apr 1, 1997·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·S M SwainR A Gams
Apr 13, 2004·Proceedings of the National Academy of Sciences of the United States of America·Andrew I SuJohn B Hogenesch
Jul 13, 2004·The New England Journal of Medicine·Steven E LipshultzStephen E Sallan
Oct 21, 2005·Basic & Clinical Pharmacology & Toxicology·Snezana K BjelogrlicSinisa Radulovic
Jan 19, 2007·American Journal of Physiology. Cell Physiology·W A LaFramboiseM J Becich
Apr 21, 2007·Nature Reviews. Cancer·Karen T LibyMichael B Sporn
May 29, 2007·American Journal of Physiology. Heart and Circulatory Physiology·Demetrios A ArvanitisEvangelia G Kranias
Dec 24, 2008·Proceedings of the National Academy of Sciences of the United States of America·Thomas E SussanShyam Biswal
May 22, 2009·Journal of Agricultural and Food Chemistry·Cristina AngeloniSilvana Hrelia
Jul 21, 2009·Progress in Cardiovascular Diseases·Mariaconsuelo Valentini, Gianfranco Parati
Sep 3, 2010·Journal of Molecular and Cellular Cardiology·Demetrios A ArvanitisEvangelia G Kranias
Mar 4, 2011·Biotechnology and Bioengineering·R J ShipleyM J Ellis
Apr 3, 2012·Journal of Molecular and Cellular Cardiology·Yanti OctaviaAn L Moens
Jul 5, 2012·Current Cardiology Reviews·Maria Volkova, Raymond Russell
Sep 8, 2012·Cellular and Molecular Life Sciences : CMLS·Jennifer England, Siobhan Loughna
Dec 12, 2012·Biochemical Pharmacology·Holly K BryanB Kevin Park
Jan 9, 2013·Annual Review of Pharmacology and Toxicology·Qiang Ma
Oct 22, 2013·Pharmacology & Therapeutics·Nima Milani-Nejad, Paul M L Janssen
Oct 30, 2013·Nature Reviews. Clinical Oncology·Steven E LipshultzTracie L Miller
Nov 12, 2013·The New England Journal of Medicine·Dick de ZeeuwUNKNOWN BEACON Trial Investigators
Feb 1, 2014·Circulation Research·Xiulan YangCharles E Murry
Aug 12, 2014·Molecular Pharmacology·Amy D HannaNicole A Beard
Sep 15, 2014·Biochemical and Biophysical Research Communications·Kaori SekineTatsuya Shimizu
Oct 18, 2014·Journal of Proteome Research·Zhen Qi LuAnthony O Gramolini
Jan 15, 2015·Annual Review of Medicine·Steven E LipshultzStephen E Sallan
Jul 21, 2015·Nature Biotechnology·Matthew J BirketChristine L Mummery
Apr 30, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Stephanie M RavenscroftJames E Sidaway
May 27, 2016·Nature Reviews. Cardiology·Milena Bellin, Christine L Mummery
May 28, 2016·Current Treatment Options in Cardiovascular Medicine·Jyothsna Akam-VenkataSteven E Lipshultz
Sep 7, 2016·British Journal of Clinical Pharmacology·Kelley K HutchinsSteven E Lipshultz
Oct 18, 2016·Toxicology Research·Harriet GaskellSteven D Webb

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cardiotoxicity

Cardiotoxicity refers to the muscle damage or dysfunction of heart electrophysiology caused by drug intake or due to disease complications. It is a well-known side effect of several cytotoxic drugs, especially of the anthracyclines and can lead to long term morbidity. Here is the latest research.