Prophylactic Evidence of MSCs-Derived Exosomes in Doxorubicin/Trastuzumab-Induced Cardiotoxicity: Beyond Mechanistic Target of NRG-1/Erb Signaling Pathway

International Journal of Molecular Sciences

Mohamed El-Sherbiny¹  Hasnaa Ali Ebrahim²  Raja El Hasnaoui Saadani²  Hajir A. Al Saihati³  Eman Abd El Aziz M. El Gebaly⁴  Nashwa Hassan Abo-Rayah⁴  Abdelmonem G. Madboly⁵  Omnia A. M. Badr⁶  Dina Sabry⁷  Rabab F. Salim⁸  Ola Mostafa⁹  Nesrine Ebrahim⁹  Sameh Abdulsamea^1,10  Nehal M. Elsherbiny^1,11  Noha Ibrahim Hussien^1,12  Amira Hassouna^1,13 

[1] Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh 11597, Saudi Arabia;Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia;Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hafr Albatin, Hafr Albatin 39524, Saudi Arabia;Department of Clinical Pharmacology, Faculty of Medicine, Benha University, Benha 13511, Egypt;Department of Forensic Medicine & Clinical Toxicology, Faculty of Medicine, Benha University, Benha 13511, Egypt;Department of Genetics and Genetic Engineering, Faculty of Agriculture, Benha University, Benha 13511, Egypt;Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Badr University in Cairo, Cairo 11562, Egypt;Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha 13511, Egypt;Department of Medical Histology and Cell Biology, Faculty of Medicine, Benha University, Benha 13511, Egypt;Department of Paediatrics, Faculty of Medicine, Benha University, Benha 13511, Egypt;Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;Department of Physiology, Faculty of Medicine, Banha University, Benha 13511, Egypt;School of Interprofessional Health Studies, Faculty of Health and Environmental Sciences, AUT University, Auckland 1010, New Zealand;

关键词: trastuzumab;    doxorubicin;    stem cells;    exosomes;    cardiac toxicity;    NRG-1;   

DOI  :  10.3390/ijms23115967

来源: DOAJ

【 摘 要 】

Trastuzumab (Trz) is a humanized monoclonal antibody targeting epidermal growth factor receptor 2 (HER2; ErbB2). The combined administration of Trz and doxorubicin (DOX) has shown potent anti-cancer efficacy; however, this regimen may be accompanied by severe cardiac toxicity. Mesenchymal stem cells (MSCs)-derived exosomes are nanosized vesicles that play a crucial role in cell–cell communication and have shown efficacy in the treatment of various diseases. In this study, we aim to investigate the cardioprotective effects of MSCs-derived exosomes in a DOX/Trz- mediated cardiotoxicity model, and the possible mechanisms underlying these effects are elucidated. Forty-nine male rats were randomly assigned into four groups: Group I (control); Group II (Dox/Trz); Group III (protective group); and Group IV (curative group). Cardiac hemodynamic parameters, serum markers of cardiac injury, oxidative stress indices, and cardiac histopathology were investigated. Further, transcript profile of specific cardiac tissue injury markers, apoptotic markers, and fibrotic markers were analyzed using qRT-PCR, while the protein expressions of pAkt/Akt, pERK/ERK, pJNK/JNK, pJNK/JNK, and pSTAT3/STAT3 were evaluated by ELISA. Additionally, cardiac mirR-21 and miR-26a were assessed. A combined administration of DOX/Trz disrupted redox and Ca²⁺ homeostasis in cardiac tissue induced myocardial fibrosis and myofibril loss and triggered cardiac DNA damage and apoptosis. This cardiotoxicity was accompanied by decreased NRG-1 mRNA expression, HER2 protein expression, and suppressed AKT and ERK phosphorylation, while triggering JNK phosphorylation. Histological and ultra-structural examination of cardiac specimens revealed features typical of cardiac tissue injury. Moreover, a significant decline in cardiac function was observed through biochemical testing of serum cardiac markers and echocardiography. In contrast, the intraperitoneal administration of MSCs-derived exosomes alleviated cardiac injury in both protective and curative protocols; however, superior effects were observed in the protective protocol. The results of the current study indicate the ability of MSCs-derived exosomes to protect from and attenuate DOX/Trz-induced cardiotoxicity. The NRG-1/HER2, MAPK, PI3K/AKT, PJNK/JNK, and PSTAT/STAT signaling pathways play roles in mediating these effects.

【 授权许可】

Unknown