In previous studies we showed that nitric oxide (NO) donors and synthetic doxorubicins (DOXs) modified with moieties containing NO-releasing groups - such as nitrooxy-DOX (NitDOX) or 3-phenylsulfonylfuroxan-DOX (FurDOX) - overcome drug resistance by decreasing the activity of ATP-binding cassette (ABC) transporters that can extrude the drug. Here we have investigated the biochemical mechanisms by which NitDOX and FurDOX exert antitumor effects. Both NitDOX and FurDOX were more cytotoxic than DOX against drug-resistant cells. Interestingly, NitDOX exhibited a faster uptake and an extranuclear distribution. NitDOX was preferentially localized in the mitochondria, where it nitrated and inhibited the mitochondria-associated ABC transporters, decreased the flux through the tricarboxylic acid cycle, slowed down the activity of complex I, lowered the synthesis of ATP, induced oxidative and nitrosative stress, elicited the release of cytochrome c and the activation of caspase-9 and -3 in DOX-resistant cells. We suggest that NitDOX may represent the prototype of a new class of multifunctional anthracyclines, which have cellular targets different from conventional anthracyclines and greater efficacy against drug-resistant tumors.

Mitochondrial-targeting nitrooxy-doxorubicin: a new approach to overcome drug resistance.

RIGANTI, Chiara;ROLANDO, Barbara;KOPECKA, JOANNA;CAMPIA, IVANA;CHEGAEV, Konstantin;LAZZARATO, Loretta;FEDERICO, ANTONELLA;FRUTTERO, Roberta;GHIGO, Dario Antonio
2013

Abstract

In previous studies we showed that nitric oxide (NO) donors and synthetic doxorubicins (DOXs) modified with moieties containing NO-releasing groups - such as nitrooxy-DOX (NitDOX) or 3-phenylsulfonylfuroxan-DOX (FurDOX) - overcome drug resistance by decreasing the activity of ATP-binding cassette (ABC) transporters that can extrude the drug. Here we have investigated the biochemical mechanisms by which NitDOX and FurDOX exert antitumor effects. Both NitDOX and FurDOX were more cytotoxic than DOX against drug-resistant cells. Interestingly, NitDOX exhibited a faster uptake and an extranuclear distribution. NitDOX was preferentially localized in the mitochondria, where it nitrated and inhibited the mitochondria-associated ABC transporters, decreased the flux through the tricarboxylic acid cycle, slowed down the activity of complex I, lowered the synthesis of ATP, induced oxidative and nitrosative stress, elicited the release of cytochrome c and the activation of caspase-9 and -3 in DOX-resistant cells. We suggest that NitDOX may represent the prototype of a new class of multifunctional anthracyclines, which have cellular targets different from conventional anthracyclines and greater efficacy against drug-resistant tumors.
MOLECULAR PHARMACEUTICS
10
1
161
174
multifunctional drugs; doxorubicin; nitric oxide; multidrug resistance; ATP-binding cassette transporters mitochondria
Chiara Riganti; Barbara Rolando; Joanna Kopecka; Ivana Campia; Konstantin Chegaev; Loretta Lazzarato; Antonella Federico; Roberta Fruttero; Dario Ghigo
File in questo prodotto:
File Dimensione Formato  
Mol_Pharm_Supporting.pdf

accesso aperto

Descrizione: Supporting Information
Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 971.25 kB
Formato Adobe PDF
971.25 kB Adobe PDF Visualizza/Apri
Mol_Pharm_manuscript.pdf

accesso aperto

Descrizione: Versione finale dell'autore
Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 1.43 MB
Formato Adobe PDF
1.43 MB Adobe PDF Visualizza/Apri
PDF_editor.pdf

non disponibili

Descrizione: PDF editoriale
Tipo di file: PDF EDITORIALE
Dimensione 808.34 kB
Formato Adobe PDF
808.34 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/129551
Citazioni
  • ???jsp.display-item.citation.pmc??? 20
  • Scopus 53
  • ???jsp.display-item.citation.isi??? 54
social impact