Novel NO-donor Doxorubicins

Doxorubicin (DOX) is an antibiotic belonging to the class of antracyclines, used for the treatment of a wide range of cancers, including hematological malignancies, many types of carcinoma, and soft tissue sarcomas. How-ever there are some serious limitation to DOX efficacy in cancer therapy. The one of them is the easy development of resistance through different mechanisms, the main of which is the overexpression of ATP-Binding Cassette (ABC) transporters, such as P-glycoprotein (Pgp), Multidrug Resistance Related Proteins (MRPs) and Breast-Cancer Resistance Related Protein (BCRP), that actively extrude drug from tumor cells. Resistance to DOX is often part of a cross-resistance towards several anticancer drugs known as Multidrug Resistance (MDR). The identification of new MDR-reversing agents selectively targeting drug-resistance cells is a field of active investigation. However so far no satisfactory reversing strategies have been identified. Some exogenous NO-donors like S-nitrosopenicillamine, sodium nitroprusside and S-nitrosoglutathione, are able to reduce the activity of Pgp and MRPs by nitration of tyrosine residues, crucial for protein functions with a consequent increase of intracellular DOX concentration and toxicity in MDR tumor cells. In previous works we demonstrated that a class of NO-donors, 1,2,5-oxadiazole 2-oxides (furoxans), was able to inhibit Pgp and MRP1 transporters in MDCK cells. Lately, our group showed that a few NO-donors linked to DOX through an ester linkage can reduce MDR in human cancer cells. These compounds were studied on doxorubicin-resistant human colon cancer cell populations (HT29-dx). This experimental model have highlighted the ability of NO-donor DOX to trigger anticancer action and to overcome the drug resistance of the cells, demonstrating that the design of NO-donor antitumor drugs could be a useful strategy to improve efficacy against drug-resistant tumors. Here we report an extended series of new NO-donor DOXs where different NO-donor moieties are linked to DOX via ester or amide linkers. All the mentioned compounds have been tested for their metabolic stability and their activity on HT29 and HT29-dx cell lines, i.e. human colon cancer cells the former being sensitive and the latter resistant to doxorubicin.