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Reversal of doxorubicin resistance by guggulsterone of Commiphora mukul in vivo
Affiliation:1. Department of Breast Surgery, the Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, China;2. Gynecological Radiotherapy, the Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, China;3. Pathology, the Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, China;1. The Second Department of Cardiology, The Third Hospital of Nanchang, Nanchang 330009, China;2. Department of Cardiology, Xi''an Central Hospital, Xi''an 710003, China;3. Ankara Yildirim Beyazit University, Faculty of Medicine, Department of Medical Pharmacology, Bilkent, Ankara, Turkey;4. Department of Pediatrics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202, USA;5. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China;1. Department of Drug Toxicology, College of Pharmacy of Guangxi Medical University, Nanning 530021, PR China;2. Department of Pharmacy, Wuhan Pulmonary Hospital, Wuhan, PR China;3. Department of Radiotherapy, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, PR China;4. Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, PR China
Abstract:Our previous study has shown co-administration of guggulsterone resulted in significant increase in chemosensitivity of multidrug-resistant human breast cancer MCF-7/DOX cells to doxorubicin (DOX) in vitro. The present study was designed to investigate whether guggulsterone had the similar modulatory activities in vivo. MCF-7/DOX and MCF-7 xenograft mice models were established. At the end of the experiment (day 28), doxorubicin treatment alone did not significantly inhibit tumor growth in MCF-7/DOX xenograft, indicating that it retained doxorubicin resistance. Whereas, doxorubicin treatment alone significantly inhibited tumor growth in MCF-7 xenograft, suggesting that it maintained doxorubicin sensitivity. When doxorubicin and guggulsterone were co-administrated, their antitumor activities were augmented in MCF-7/DOX xenograft. However, combination therapy did not enhance the antitumor effects of doxorubicin in MCF-7 xenograft. The expression of proliferative cell nuclear antigens PCNA and Ki67 after doxorubicin treatment alone was not significantly different from that of vehicle group in MCF-7/DOX xenograft. On the contrary, doxorubicin treatment alone significantly reduced PCNA and Ki67 expression in MCF-7 xenograft. Combination therapy also significantly reduced PCNA and Ki67 expression in MCF-7/DOX xenograft, compared to doxorubicin treatment alone. However, combination therapy did not enhance the inhibitory effects of doxorubicin on PCNA and Ki67 expression in MCF-7 xenograft. Examining the apoptotic index by TUNEL assay showed similar results. Further studies demonstrated the inhibitory effects of guggulsterone on Bcl-2 and P-glycoprotein expression were the possible reason to increase chemosensitivity of MCF-7/DOX cells to doxorubicin in vivo. Examining body weight, hematological parameters, hepatic, cardiac and gastrointestinal tracts histopathology revealed that no significant signs of toxicity were related to guggulsterone. Guggulsterone might reverse doxorubicin resistance in vivo, with no severe side effects.
Keywords:Guggulsterone  Xenograft  Doxorubicin  Drug-resistance
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