Induction of caspase-independent apoptotic-like cell death of mouse mammary tumor TA3Ha cells in vitro and reduction of their lethality in vivo by the novel chemotherapeutic agent GIT-27NO

Free Radical Biology & Medicine
Sanja A MijatovicFerdinando Nicoletti

Abstract

The new chemical entity GIT-27NO was created by the covalent linkage of a NO moiety to the anti-inflammatory isoxazoline VGX-1027. The compound has been shown to possess powerful anticancer effects both in vitro and in vivo. However, its effects on nonsolid and metastatic forms of tumors have not yet been investigated. We have studied the effects of GIT-27NO on the highly invasive mouse mammary TA3Ha cell line in vitro and in vivo. In contrast to the conventional exogenous NO donor sodium nitroprusside, GIT-27NO successfully enhanced intracellular NO concentration in TA3Ha cells. Intracellular accumulation of NO was followed by marked decrease in TA3Ha cell viability accompanied by typical apoptotic features. Interestingly, inverted membrane phosphatidylserine residues, reduced volume of nucleus, condensed chromatin, and terminal fragmentation of DNA were associated with inhibited caspase-3 activity and transcription of the genes encoding caspase-3, -8, and -9. In parallel, GIT-27NO rapidly but transiently prevented the loss of p53 through phosphorylation on Ser 20 and provided the necessary signals for the execution of downstream processes without p53 de novo synthesis. The caspase-independent apoptotic-like death process trig...Continue Reading

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Citations

Dec 19, 2015·Nature Reviews. Drug Discovery·Csaba Szabo
Jul 6, 2012·Basic & Clinical Pharmacology & Toxicology·Paolo FagoneFerdinando Nicoletti
Mar 31, 2017·Antioxidants & Redox Signaling·Sung-Won ShinWon Park
Jul 13, 2019·International Journal of Immunopathology and Pharmacology·Katia ManganoAntonio Di Cataldo
Jul 17, 2012·Molecular Pharmacology·Marija MojicFerdinando Nicoletti
May 6, 2020·Antioxidants·Sanja MijatovićDanijela Maksimović-Ivanić
Mar 5, 2013·Oncotarget·James A McCubreyZoya N Demidenko
Jul 18, 2018·European Journal of Pharmacology·Paolo FagoneFerdinando Nicoletti

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