Journal
MOLECULAR PHARMACEUTICS
Volume 10, Issue 1, Pages 161-174Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp300311b
Keywords
multifunctional drugs; doxorubicin; nitric oxide; multidrug resistance; ATP-binding cassette transporters; mitochondria
Funding
- Italian Ministry of University and Research
- Fondazione Internazionale Ricerche Medicina Sperimentale (FIRMS)
- Compagnia di San Paolo (Progetto Oncologia)
- Italian Association for Cancer Research (AIRC) [MFAG 11475]
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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, and 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.
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