Shikonin causes apoptosis by disrupting intracellular calcium homeostasis and mitochondrial function in human hepatoma cells
Affiliations: Department of Food Nutrition, College of Food Science and Engineering, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China, Department of Animal Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, P.R. China
- Published online on: December 5, 2017 https://doi.org/10.3892/etm.2017.5591
- Pages: 1484-1492
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
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Shikonin is known to suppress proliferation and induce apoptosis in a variety of cancer cell lines. In the present study, SMMC‑7721 human hepatocellular carcinoma cells were treated with shikonin (1, 2 or 4 µM) for 12‑48 h. Cell morphological alterations and DNA damage were determined. Furthermore, changes in cell cycle, mitochondrial transmembrane potential, calcium homeostasis and levels of reactive oxygen species were measured. Shikonin‑treated SMMC‑7721 cells exhibited morphological changes and DNA damage. Shikonin inhibited cell proliferation causing cell cycle arrest at the G0/G1 phase and induced apoptosis in a dose‑ and time‑dependent manner. Shikonin‑induced apoptosis was associated with activation of caspases‑3, ‑8 and ‑9, elevated levels of intracellular Ca2+ and reactive oxygen species, reduced mitochondrial membrane potential and enhanced efflux of Ca2+ and K+. Gene expression B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax), p53 and caspase‑3 was up‑regulated, whereas Bcl‑2 expression was downregulated. Shikonin caused apoptosis by inhibiting cell cycle progression, disrupting Ca2+ homeostasis, inducing oxidative stress and triggering mitochondrial dysfunction. Activation of caspases‑3, ‑8 and ‑9, K+ efflux, and regulation of Bax, Bcl‑2, p53 and caspase‑3 expression are involved in the process. These results provide in‑depth insight into the mechanisms of action of shikonin in the treatment of cancer.