Planta Med 2014; 80 - P1L71
DOI: 10.1055/s-0034-1394728

Mechanistic study on the cardioprotective and chemosensitizing effects of a novel danshensu derivative

L Wang 1, L Shan 2, G Cui 1, Y Chen 1, J li 1, Q Zhang 1, MPM Hoi 1, Y Wang 2 SMY Lee 1, et al
  • 1State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Tomás Pereira S.J., Macao, 999078, China
  • 2Institute of New Drug Research, Collage of Pharmacy, Jinan University, Guangzhou, 510632, China

Doxorubicin (Dox) is an anthracycline antibiotic which is widely used in clinics as an anticancer agent. However, the use of Dox is limited by its cardiotoxicity. Our previous studies have shown that a Danshensu derivative ADTM displayed strong cardioprotective effects in an oxidative stress-induced cell injury model in H9c2 cardiomyocytes and an acute myocardial ischemia model in rat [1]. We are developing more potent cardioprotective danshensu derivative based on ADTM structure for management of the cardiotoxic side effect of Dox. In the present study, we investigated the protective and chemosensitizing effects of a novel Danshensu derivative D006 against cardiotoxicity induced by Dox and in increasing the antitumor activity of Dox respectively. Our results showed that D006 was approximately 30-fold more potent than ADTM in ameliorating Dox-induced cardiotoxicity in H9c2 cells. In the zebrafish model, D006 but not ADTM or Danshensu alone, significantly preserved stroke volume of heart function after Dox treatment. In addition, D006 enhanced Dox-induced apoptosis as well as ROS production in MCF-7 tumor cells. Mitochondrial biogenesis, a process involved in the formation of new mitochondrial, which depends on the expression of PGC-1. Recent studies showed that suppressed cardiac mitochondrial biogenesis and decreased mtDNA contents may play vital roles in the pathogenesis of Dox induced cardiomyopathy [2]. Further mechanistic studies verified that D006 increased the expression of PGC-1β in H9c2 cells. Moreover, D006 upregulated mitochondrial biogenesis and increased mtDNA copy number after Dox treatment in H9c2 cells. Our results revealed that a new danshensu derivative displayed promising cardioprotective effects against Dox induced cardiotoxicity both in vivo and in vitro, at least partially through activating mitochondrial biogenesis. In addition, the new danshensu derivative also potentiated the anticancer effects of Dox in breast tumor cells.

Keywords: danshensu, doxorubicin, cardioprotection, mitochondrial biogenesis, anticancer

References:

[1] Cui, G. et al. (2013) Int J Cardiol 168(2):1349 – 59.

[2] Miyagawa, K. et al. (2010) Hypertension.2010 55(3):738 – 46.