A library of nitric oxide-donor doxorubicins (NO-DOXOs) was synthesized by linking appropriate NO-donor moieties at C-14 position through an ester bridge. Their hydrolytic stability was evaluated. The intracellular accumulation and cytotoxicity of these novel NO-DOXOs were studied in DOXO-sensitive (HT29) and DOXO-resistant (HT29/dx) tumor-cells. Hydrolytically-stable compounds accumulated in HT29 and HT29/dx cells, thanks to the nitration of plasma-membrane efflux transporters. Surprisingly, no close correlation was found between intracellular accumulation and cytotoxicity. Only compounds with high mitochondria retention (due to nitration of mitochondrial efflux transporter) exert high cytotoxicity, through the activation of a mitochondrial-dependent apoptosis.

Overcoming multidrug resistance by targeting mitochondria with NO-donating doxorubicins

GAZZANO, Elena;CHEGAEV, Konstantin;ROLANDO, Barbara;BLANGETTI, Marco;GHIGO, Dario Antonio;FRUTTERO, Roberta;RIGANTI, Chiara
2016

Abstract

A library of nitric oxide-donor doxorubicins (NO-DOXOs) was synthesized by linking appropriate NO-donor moieties at C-14 position through an ester bridge. Their hydrolytic stability was evaluated. The intracellular accumulation and cytotoxicity of these novel NO-DOXOs were studied in DOXO-sensitive (HT29) and DOXO-resistant (HT29/dx) tumor-cells. Hydrolytically-stable compounds accumulated in HT29 and HT29/dx cells, thanks to the nitration of plasma-membrane efflux transporters. Surprisingly, no close correlation was found between intracellular accumulation and cytotoxicity. Only compounds with high mitochondria retention (due to nitration of mitochondrial efflux transporter) exert high cytotoxicity, through the activation of a mitochondrial-dependent apoptosis.
BIOORGANIC & MEDICINAL CHEMISTRY
24
5
967
975
http://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry/
Doxorubicin; Mitochondria; Multidrug resistance; Nitric oxide; Biochemistry; Clinical Biochemistry; Molecular Biology; Molecular Medicine; Organic Chemistry; Drug Discovery3003 Pharmaceutical Science; 3003
Gazzano, Elena; Chegaev, Konstantin; Rolando, Barbara; Blangetti, Marco; Annaratone, Lorenzo; Ghigo, Dario; Fruttero, Roberta; Riganti, Chiara
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1556538
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