Synergistic inhibition of leukemia WEHI-3 cell growth by arsenic trioxide and Hedyotis diffusa Willd extract in vitro and in vivo
Affiliations: Graduate Institute of Chinese Medicine, China Medical University, Taichung 40402, Taiwan, R.O.C., Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, Taichung 40402, Taiwan, R.O.C., Department of Biological Sciences and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan, R.O.C., Department of Health and Nutrition Biotechnology, College of Health Science, Asia University, Taichung 41354, Taiwan, R.O.C.
- Published online on: April 27, 2017 https://doi.org/10.3892/etm.2017.4392
- Pages: 3388-3396
Copyright: © Kuo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
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Arsenic trioxide (ATO) is clinically used to treat acute promyelocytic leukemia (APL); however, the therapeutic dose of ATO may prompt critical cardiac side effects. Combination therapy may be used to improve the therapeutic efficiency. To evaluate this possibility, the present study determined the combined effects of Hedyotis diffusa Willd (HDW) extract and ATO in leukemic WEHI‑3 cells. The results demonstrated that co‑treatment of HDW with ATO resulted in a synergistic augmentation of cytotoxicity in cells at the concentration tested. In order to investigate the potential therapeutic application for leukemia, the combined effects of HDW and ATO were analyzed on the WEHI‑3 cell‑induced orthotopic leukemia animal model in vivo. The WEHI‑3 cells in mice with leukemia were established by injecting murine WEHI‑3 cells into BALB/c mice, and treating them with HDW and/or combined with ATO. The results indicated that HDW alone or HDW combined with ATO promoted the total survival rate of mice with leukemia, and these effects are dose‑dependent. HDW alone or HDW combined with ATO did not affect the body weight, decreased the spleen weight and did not affect the liver weight. Furthermore, the results demonstrated that HDW alone or HDW combined with ATO resulted in a synergistic augmentation of apoptosis in WEHI‑3 cells at the concentration tested. In order to further reveal the detailed mechanism of this synergistic effect on apoptosis, apoptosis‑related proteins were also evaluated. The data revealed that HDW alone or HDW combined with ATO induced the expression of death receptor 4 (DR4) and DR5 and the activation of poly adenosine diphosphate ribose polymerase, caspase‑3, ‑8 and ‑9. Furthermore, HDW alone or HDW combined with ATO decreased the expression levels of B‑cell lymphoma 2, B‑cell lymphoma‑extra large and survivin, and increased the expression levels of Bak and t‑Bid. Altogether, the results indicate that the combination of HDW with ATO may be a promising strategy used to increase the clinical efficacy of ATO in the treatment of APL.