Mitochondrial-targeting nitrooxy-doxorubicin: effects on P-glycoprotein and assessment of their vascular effects

ATP binding cassette (ABC) transporters can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. Synthetic doxorubicins modified with moieties containing NO-releasing groups (NitDOX) overcome drug resistance by nitrating critical tyrosine residues of ABC transporters. The introduction of a NO-releasing group made NitDOX also a functionally distinct anthracycline, which pharmacologic properties widely different from the parent drug. NitDOX in fact, accumulates preferentially in the mitochondria, where it affects critical steps of mitochondrial metabolism. The development of clinically useful MDR inhibitors remains a promising strategy for addressing and potentially overcoming MDR. Drug safety, however, is one of the main causes of discontinuation or withdrawal of novel drugs and many reports indicate that cardiovascular toxicity is a significant driver, being more frequent, for example, than hepatotoxicity. In order to develop novel and safe MDR inhibitors and by considering the potential use of NitDOX as innovative drugs, the aim of this study was to characterize the mechanism of action and vascular effects of the novel P-gp inhibitors especially when considering the role of NO in the regulation of vascular tone. Their effects were compared to those of doxorubicin (DOXO) and tariquidar, one of the most potent P-gp inhibitors. Results demonstrated that NitDOX was less toxic than DOXO in human endothelial cells at concentrations comparable to those effective to exert antitumor activities and to accumulate in drug-resistant cells. Both NitDOX and DOXO, however, promoted similar cytotoxic and apoptotic effects in vascular smooth muscle cells, while tariquidar were mostly inactive. In conclusion, NitDOX is a functionally distinct anthracycline, with a more favorable toxicity profile and a better efficacy against drug-resistant cells. In the context of earlier attempts to use NO delivery strategies in cancer therapy, NitDOX is worthy of further investigations in preclinical and clinical settings. This work was supported by MIUR (Futuro In Ricerca 2012, RBFR12SOQ1)