Differential mechanistic investigation of protective effects from imperatorin and sec-O-glucosylhamaudol against arsenic trioxide-induced cytotoxicity in vitro. (December 2016)

• Record Type: Journal Article
• Authors: Hu, Liufang; Sun, Jianhui; Li, Hongmei; Wang, Lifang; Wei, Yuna; Wang, Ying; Zhu, Yaying; Huo, Hairu; Tan, Yuqing
• Is Part Of: Toxicology in vitro. Volume 37(2017)
• Page Start: 97
• Page End: 105
• Publication Date: 2016-12
• Subjects: As2O3-induced cytotoxicity -- Imperatorin -- sec-O-glucosylhamaudol -- Mechanisms; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2016.09.002
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: Background and purpose: The clinical use of arsenic trioxide (As2 O3 ) for treating acute promyelocytic leukemia (APL) is limited due to its severe cardiotoxicity. The possible mechanisms of As2 O3 -induced cardiotoxicity include DNA fragmentation, reactive oxygen species (ROS) generation, cardiac ion channel changes and apoptosis. The present study is designed to investigate the protective effects of imperatorin and sec - O -glucosylhamaudol and to explore their mechanistic involvement in As2 O3 -induced cytotoxicity. Experimental methods: Cell viability assay, Lactate dehydrogenase (LDH) release, Acridine orange/ethidium bromide (AO/EB) double staining, Caspase-3 activity assay, ROS generation, cellular calcium levels, mRNA expression levels by qRT-PCR and protein expression levels by Western blotting were measured in H9c2 cells in combination with As2 O3 and imperatorin or sec - O -glucosylhamaudol. Key results: We observed that H9c2 cells treated with imperatorin or sec - O -glucosylhamaudol were more resistant to As2 O3 -induced cell death. Both imperatorin and sec - O -glucosylhamaudol reduced H9c2 cell apoptosis, but both imperatorin and sec - O -glucosylhamaudol had no effects on Caspase-3 activity and intracellular calcium accumulation. Furthermore, imperatorin was capable of suppressing ROS generation, while sec - O -glucosylhamaudol did not show this effect. Moreover, imperatorin and sec - O -glucosylhamaudol triggered Nrf2 activation, which resulted in upregulation of downstream phase II metabolic enzymes and antioxidant protein/enzyme, probably offering cellular protection to As2 O3 -induced cardiotoxicity via the Nrf2 signal pathway. Conclusions and implications: Imperatorin and sec - O -glucosylhamaudol can ameliorate As2 O3 -induced cytotoxicity and apoptosis in H9c2 cells, the mechanisms probably related to antioxidation. As2 O3 in combination with imperatorin or sec - O -glucosylhamaudol could be considered as a novel strategy to expand the clinical application of As2 O3 . Highlights: The new pharmacological action of traditional Chinese medicine Radix Saposhnikoviae Imperatorin can ameliorate As2 O3 -induced cytotoxicity and apoptosis in H9c2 cells. sec - O -glucosylhamaudol can ameliorate As2 O3 -induced cytotoxicity and apoptosis in H9c2 cells. A novel strategy to expand the clinical application of As2 O3