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Updated: May 21, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Prevention of Doxorubicin cardiopathic changes by a benzyl styryl sulfone in mice
Min Lu1, Salim Merali, Ronald Gordon
1Mount Sinai School of Medicine, New York, NY, USA.
Abstract:
Cardiac toxicity is a major limitation in the use of doxorubicin (and related anthracyclins). ON 1910.Na (Estybon, Rogersitib, or 1910), a substituted benzyl styryl sulfone, is equally active as doxorubicin against MCF-7 human mammary carcinoma xenografted into nude mice. 1910 augments the antitumor activity of doxorubicin when given simultaneously. Furthermore, when given in combination, 1910 protects against cardiac weight loss and against morphological damage to cardiac tissues. Doxorubicin induces inactivation of glucose response protein 78 (GRP78), a principal chaperone that serves as the master regulator of the unfolded protein response (UPR). Inactivated GRP78 leads to an increase in misfolded proteins, endoplasmic reticulum (ER) stress, activation of UPR sensors, and increased CHOP expression. 1910 prevents the inactivation of GRP78 by doxorubicin, and the combination, while more active against the tumor, protects against cardiac weight loss.
Insights
ON 1910.Na enhances doxorubicin
Area of Science:
- Oncology
- Cardiology
- Molecular Biology
Background:
- Doxorubicin, a widely used chemotherapy agent, exhibits significant cardiac toxicity, limiting its clinical application.
- Cardiac dysfunction is a major dose-limiting side effect of anthracycline chemotherapy.
- The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress are implicated in doxorubicin-induced cardiotoxicity.
Purpose of the Study:
- To evaluate the efficacy and cardiotoxicity of ON 1910.Na as a potential adjuvant to doxorubicin.
- To investigate the protective mechanisms of ON 1910.Na against doxorubicin-induced cardiac damage.
- To explore the role of glucose response protein 78 (GRP78) and the UPR in the observed effects.
Main Methods:
- MCF-7 human mammary carcinoma xenograft model in nude mice.
- Administration of doxorubicin alone, ON 1910.Na alone, and in combination.
- Assessment of tumor growth inhibition, cardiac weight, cardiac tissue morphology, and GRP78/UPR pathway markers.
Main Results:
- ON 1910.Na demonstrated comparable antitumor activity to doxorubicin against MCF-7 xenografts.
- The combination therapy significantly augmented doxorubicin's antitumor efficacy.
- ON 1910.Na treatment prevented doxorubicin-induced cardiac weight loss and morphological damage, while preserving GRP78 activity and mitigating ER stress.
Conclusions:
- ON 1910.Na is a promising agent that enhances doxorubicin's antitumor effects while protecting against its cardiotoxicity.
- The protective effect is associated with the prevention of GRP78 inactivation and subsequent ER stress.
- This combination strategy offers a potential therapeutic approach to improve the efficacy and safety of anthracycline-based chemotherapy.
