H₂S-Donating Doxorubicins May Overcome Cardiotoxicity and Multidrug Resistance

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.

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors

“…The ADT-OH H 2 S-releasing group has also been used to derivatize a variety of additional clinically used drugs including the N-methyl-D-aspartate receptor antagonists memantin and amantadine (Marutani et al, 2014), the antistroke compound 3-n-butylphthalide Yin et al, 2016), doxorubicin (Chegaev et al, 2016), olenoic acid (Xu et al, 2016a), glycyrrhetic acid (Song et al, 2016), nicotinic acid (Sun et al, 2016b), naproxen, as an amide derivative resistant to hydrolysis (Hammers et al, 2016), valproic acid (Hammers et al, 2016), losartan (Martelli et al, 2012), and the Chinese traditional compound Danshensu [b-(3, 4-dihydroxyphenyl)lactic acid] (Yan et al, 2017). Most of these compounds remain to be further characterized with respect to their pharmacological effects in vitro and in vivo.…”

Toward Hydrogen Sulfide Based Therapeutics: Critical Drug Delivery and Developability Issues

“…demonstrated that exogenous H 2 S (NaHS) attenuates doxorubicin (DOX) induced cytotoxic effects in H9c2 cardiac cells through the PI3K/Akt/FoxO3a pathway. During the same period, Chegaev et al . reported a series of H 2 S‐releasing doxorubicin analogs (H 2 S‐DOXs) by combining DOX with an appropriate H 2 S donor substructure (Fig.…”

Protective Mechanism of Hydrogen Sulfide against Chemotherapy-Induced Cardiotoxicity

“…Moreover, Chegaev et al reported a series of new doxorubicin derivatives (H 2 S-DOXOs), which combined doxorubicin with appropriate H 2 S donor substructures. These H 2 S-releasing doxorubicins were safe and effective at 5 μM concentration on H9c2 cells, without any toxicity (Chegaev et al, 2016 ). They observed that a few compounds even could trigger high activity on the cancer cells and might be used to take the place of naked doxorubicin in the future.…”