Doxorubicin (DOXO) is one of the most effective antineoplastic agents in clinical practice. Its use is limited by acute and chronic side effects, in particular by its cardiotoxicity and by the rapid development of resistance to it. As part of a program aimed at developing new DOXO derivatives endowed with reduced cardiotoxicity, and active against DOXO-resistant tumor cells, a series of H2S-releasing DOXOs (H2S-DOXOs) were obtained by combining DOXO with appropriate H2S donor substructures. The resulting compounds were studied on H9c2 cardiomyocytes and in DOXO-sensitive U-2OS osteosarcoma cells, as well as in related cell variants with increasing degrees of DOXO-resistance. Differently from DOXO, most of the products were not toxic at 5 μM concentration on H9c2 cells. A few of them triggered high activity on the cancer cells. H2S-DOXOs 10 and 11 emerged as the most interesting members of the series. The capacity of 10 to impair Pgp transporter is also discussed.

H2S-Donating Doxorubicins May Overcome Cardiotoxicity and Multidrug Resistance

CHEGAEV, Konstantin;ROLANDO, Barbara;CORTESE, DANIELA;GAZZANO, Elena;BUONDONNO, ILARIA;LAZZARATO, Loretta;RIGANTI, Chiara;FRUTTERO, Roberta;GHIGO, Dario Antonio;GASCO, Alberto
2016

Abstract

Doxorubicin (DOXO) is one of the most effective antineoplastic agents in clinical practice. Its use is limited by acute and chronic side effects, in particular by its cardiotoxicity and by the rapid development of resistance to it. As part of a program aimed at developing new DOXO derivatives endowed with reduced cardiotoxicity, and active against DOXO-resistant tumor cells, a series of H2S-releasing DOXOs (H2S-DOXOs) were obtained by combining DOXO with appropriate H2S donor substructures. The resulting compounds were studied on H9c2 cardiomyocytes and in DOXO-sensitive U-2OS osteosarcoma cells, as well as in related cell variants with increasing degrees of DOXO-resistance. Differently from DOXO, most of the products were not toxic at 5 μM concentration on H9c2 cells. A few of them triggered high activity on the cancer cells. H2S-DOXOs 10 and 11 emerged as the most interesting members of the series. The capacity of 10 to impair Pgp transporter is also discussed.
59
4881
4889
http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00184
Chegaev, Konstantin; Rolando, Barbara; Cortese, Daniela; Gazzano, Elena; Buondonno, Ilaria; Lazzarato, Loretta; Fanelli, Marilù; Hattinger, Claudia M; Serra, Massimo; Riganti, Chiara; Fruttero, Roberta; Ghigo, Dario; Gasco, Alberto
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1570043
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