H2S-Donating Doxorubicins May Overcome Cardiotoxicity and Multidrug Resistance.
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.
Department of Science and Drug Technology, University of Torino , via Pietro Giuria 9, 10125 Torino, Italy.
Konstantin
K
Chegaev
Department of Science and Drug Technology, University of Torino , via Pietro Giuria 9, 10125 Torino, Italy.
Barbara
B
Rolando
Department of Science and Drug Technology, University of Torino , via Pietro Giuria 9, 10125 Torino, Italy.
Daniela
D
Cortese
Department of Oncology and Center for Experimental Research and Medical Studies (CeRMS), University of Torino , via Santena, 5/bis, 10126 Torino, Italy.
Elena
E
Gazzano
Department of Oncology and Center for Experimental Research and Medical Studies (CeRMS), University of Torino , via Santena, 5/bis, 10126 Torino, Italy.
Ilaria
I
Buondonno
Department of Science and Drug Technology, University of Torino , via Pietro Giuria 9, 10125 Torino, Italy.
Loretta
L
Lazzarato
Orthopaedic Rizzoli Institute, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit , via G. C. Pupilli 1, 40136 Bologna, Italy.
Marilù
M
Fanelli
Orthopaedic Rizzoli Institute, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit , via G. C. Pupilli 1, 40136 Bologna, Italy.
Claudia M
CM
Hattinger
Orthopaedic Rizzoli Institute, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit , via G. C. Pupilli 1, 40136 Bologna, Italy.
Massimo
M
Serra
Department of Oncology and Center for Experimental Research and Medical Studies (CeRMS), University of Torino , via Santena, 5/bis, 10126 Torino, Italy.
Chiara
C
Riganti
Department of Science and Drug Technology, University of Torino , via Pietro Giuria 9, 10125 Torino, Italy.
Roberta
R
Fruttero
Department of Oncology and Center for Experimental Research and Medical Studies (CeRMS), University of Torino , via Santena, 5/bis, 10126 Torino, Italy.
Dario
D
Ghigo
Department of Science and Drug Technology, University of Torino , via Pietro Giuria 9, 10125 Torino, Italy.
Alberto
A
Gasco
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism* / Q000494:pharmacology; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects*; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D006862:Hydrogen Sulfide