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A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
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H2S-Donating Doxorubicins May Overcome Cardiotoxicity and Multidrug Resistance

Konstantin Chegaev1, Barbara Rolando1, Daniela Cortese1

  • 1Department of Science and Drug Technology, University of Torino , via Pietro Giuria 9, 10125 Torino, Italy.

Journal of Medicinal Chemistry
|April 28, 2016
PubMed

Insights

New hydrogen sulfide-releasing doxorubicin (DOXO) derivatives show reduced cardiotoxicity and activity against resistant cancer cells. Compounds H2S-DOXOs 10 and 11 are particularly promising for improved chemotherapy.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Cardiology

Background:

  • Doxorubicin (DOXO) is a potent antineoplastic agent but faces limitations due to cardiotoxicity and drug resistance.
  • Developing DOXO derivatives with reduced side effects and efficacy against resistant tumors is crucial for advancing cancer therapy.

Purpose of the Study:

  • To synthesize and evaluate novel hydrogen sulfide-releasing DOXO derivatives (H2S-DOXOs).
  • To assess the cardiotoxicity and anticancer activity of H2S-DOXOs against sensitive and resistant cancer cell lines.

Main Methods:

  • Synthesis of H2S-DOXO compounds by conjugating DOXO with H2S donor moieties.
  • In vitro evaluation of cytotoxicity on H9c2 cardiomyocytes and U-2OS osteosarcoma cells (sensitive and resistant variants).

Main Results:

  • Most synthesized H2S-DOXOs exhibited significantly lower toxicity on H9c2 cardiomyocytes compared to DOXO.
  • Several H2S-DOXO compounds demonstrated potent anticancer activity against DOXO-resistant cells.
  • H2S-DOXOs 10 and 11 were identified as lead compounds with promising therapeutic potential.

Conclusions:

  • H2S-DOXO derivatives represent a promising strategy to overcome DOXO-induced cardiotoxicity and drug resistance.
  • Compounds 10 and 11 warrant further investigation for their potential as next-generation anticancer agents.

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