Multitarget Drugs: No-Donor Doxorubicins

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Poster communications

259

PC173

Multitarget Drugs: No-Donor Doxorubicins.

.RQVWDQWLQ&KHJDHYa_{Chiara Riganti,}b_{Elena Gazzano,}b_{Barbara Rolando,}a_{Roberta Fruttero,}a,*_{Alberto Gasco}a

a_{Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, via P. Giuria, 9, 10125 Torino, Italy;} b_{Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, via Santena 5/bis, 10126 Torino, Italy.}

*[email protected]

Doxorubicin (DOXO) is an antibiotic belonging to the class of anthracyclines, used in treating a wide range of cancers, including hematological malignancies, many types of carcinoma, and soft tissue sarcomas. However, WKHUHDUHVRPHVHULRXVOLPLWDWLRQVRQ'2;2¶VHI¿FDF\LQFDQFHUWKHUDS\2QHLVWKHUHDG\GHYHORSPHQWRIUH-sistance through different mechanisms, the main one being 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), which actively extrude the drug from tumor cells. Resistance to DOXO is

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EXWQRVDWLVIDFWRU\UHYHUVLQJVWUDWHJLHVKDYH\HWEHHQLGHQWL¿HG[2]_{In previous research our group showed that}

QLWULFR[LGH12FDQUHGXFH0'5LQKXPDQFDQFHUFHOOV6RPHH[RJHQRXV12GRQRUVOLNH6QLWURVRSHQLFLO-lamine, sodium nitroprusside, and S-nitrosoglutathione, were able to reduce the activity of Pgp and MRPs, by nitrating tyrosine residues crucial for protein functions, with consequent increase of intracellular DOXO

concen-tration and toxicity in MDR tumor cells.[3]_{On this basis, new semisynthetic doxorubicines have been designed,}

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In order to extend this new class of semisynthetic DOXO, a small library of novel chimeras of DOXO were de-signed, bearing different NO-donor groups at the C-14 position (Fig. 1). Their toxicity against human DOXO-sen- VLWLYHFRORQFDQFHU+7FHOOVDQGDJDLQVW'2;2UHVLVWDQW+7G[FHOOVZDVVWXGLHGIRUWKHPRVWDFWLYHFRP-pounds, the localization and putative mechanisms of toxicity in DOXO-resistant cells were also investigated.

References

1. 7DNDUD.6DNDHGD72NXPXUD.Curr. Pharm. Des. , 12, 273-286. 2. 7UN'+DOO0'&KX%)HWDOCancer Res. , 69, 8293-8301. 3. _{Riganti, C.; Miraglia, E.; Viarisio, D. et. al., Cancer Res.}, 65(2), 516-525.