Doxorubicin (DOX), also known as Adriamiycin, is an antibiotic belonging to the class of antracyclines, widely used for the treatment of solid and hematological malignancies. The major limitation to DOX efficacy in cancer therapy is the easy development of the resistance through different mechanisms, the main of which is the overexpression of ATP-Binding Cassette (ABC) transporters, such as P-glycoprotein (Pgp/ABCB1), Multidrug Resistance related Proteins (MRPs/ABCCs) and Breast-Cancer Resistance related Protein (BCRP/ABCG2), that actively extrude the drug from tumor cells. Resistance to DOX is often part of a cross-resistance towards several anti-cancer drugs known as Multidrug Resistance (MDR) [1]. The identification of new MDR-reversing agents selectively targeting drug-resistance cells is a field of active investigation, but until now no satisfactory reversing strategies have been identified [2]. Previous works from our group showed that nitric oxide can reduce MDR in human cancer cells. By nitrating critical tyrosines of Pgp/ABCB1 and MRPs/ABCCs, NO donors like S-nitrosopenicillamine, sodium nitroprusside and S-nitrosoglutathione, reduce the activity of pumps and increases intracellular DOX accumulation and toxicity in MDR tumors [3]. Also furoxans derivatives (1,2,5-oxadiazole 2-oxides), NO-donors under the action of thiol cofactors, inhibit Pgp/ABCB1 and MRP1/ABCC1 transporters in MDCK cells, increasing the retention of DOX [4]. On these bases, we have recently designed new DOXO derivatives in which the antibiotic was joined through an ester linkage to NO-donor moieties containing either 3-phenylsulfonylfuroxan or nitrooxy substructures [5]. These compounds were studied on doxorubicin-resistant human colon cancer cell populations (HT29-dx). This experimental model have highlighted the ability of NO-donor doxorubicins 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.
NITRIC OXIDE DONOR DOXORUBICINS: A USEFUL STRATEGY TO ADDRESS THE PROBLEM OF MDR IN CANCER THERAPY
ROLANDO, Barbara;RIGANTI, Chiara;CHEGAEV, Konstantin;FRUTTERO, Roberta;GASCO, Alberto
2012-01-01
Abstract
Doxorubicin (DOX), also known as Adriamiycin, is an antibiotic belonging to the class of antracyclines, widely used for the treatment of solid and hematological malignancies. The major limitation to DOX efficacy in cancer therapy is the easy development of the resistance through different mechanisms, the main of which is the overexpression of ATP-Binding Cassette (ABC) transporters, such as P-glycoprotein (Pgp/ABCB1), Multidrug Resistance related Proteins (MRPs/ABCCs) and Breast-Cancer Resistance related Protein (BCRP/ABCG2), that actively extrude the drug from tumor cells. Resistance to DOX is often part of a cross-resistance towards several anti-cancer drugs known as Multidrug Resistance (MDR) [1]. The identification of new MDR-reversing agents selectively targeting drug-resistance cells is a field of active investigation, but until now no satisfactory reversing strategies have been identified [2]. Previous works from our group showed that nitric oxide can reduce MDR in human cancer cells. By nitrating critical tyrosines of Pgp/ABCB1 and MRPs/ABCCs, NO donors like S-nitrosopenicillamine, sodium nitroprusside and S-nitrosoglutathione, reduce the activity of pumps and increases intracellular DOX accumulation and toxicity in MDR tumors [3]. Also furoxans derivatives (1,2,5-oxadiazole 2-oxides), NO-donors under the action of thiol cofactors, inhibit Pgp/ABCB1 and MRP1/ABCC1 transporters in MDCK cells, increasing the retention of DOX [4]. On these bases, we have recently designed new DOXO derivatives in which the antibiotic was joined through an ester linkage to NO-donor moieties containing either 3-phenylsulfonylfuroxan or nitrooxy substructures [5]. These compounds were studied on doxorubicin-resistant human colon cancer cell populations (HT29-dx). This experimental model have highlighted the ability of NO-donor doxorubicins 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.
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