Abstract
According to the potential anti-hepatoma therapeutic effect of Schisandra chinensis polysaccharides presented in previous studies, a bioactive constituent, homogeneous Schisandra chinensis polysaccharide-0-1 (SCP-0-1), molecular weight (MW) circa 69.980 kDa, was isolated and purified. We assessed the efficacy of SCP-0-1 against human hepatocellular liver carcinoma (HepG2) cells to investigate the effects of its antitumour activity and molecular mechanisms. Anticancer activity was evaluated using microscopy, 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyltetrazolium bromide (MTT) assay, Hoechst 33258 staining, acridine orange (AO) staining, flow cytometry (FCM), and cell-cycle analysis. SCP-0-1 inhibited the HepG2 cells’ growth via inducing apoptosis and second gap/mitosis (G2/M) arrest dose-dependently, with a half maximal inhibitory concentration (IC50) value of 479.63 µg/mL. Western blotting of key proteins revealed the apoptotic and autophagic potential of SCP-0-1. Besides, SCP-0-1 upregulated Bcl-2 Associated X Protein (Bax) and downregulated B-cell leukemia/lymphoma 2 (Bcl-2) in the HepG2 cells. The expression of caspase-3, -8, and -9; poly (ADP-ribose) polymerase (PARP); cytochrome c (Cyt C); tumor protein 53 (p53); survivin; sequestosome 1 (p62); microtubule-associated protein 1 light chain-3B (LC3B); mitogen-activated protein kinase p38 (p38); extracellular regulated protein kinases (ERK); c-Jun N-terminal kinase (JNK); protein kinase B (AKT); and heat shock protein 90 (Hsp90) were evaluated using Western blotting. Our findings demonstrate a novel mechanism through which SCP-0-1 exerts its antiproliferative activity and induces mitochondrial apoptosis rather than autophagy. The induction of mitochondrial apoptosis was attributed to the inhibition of the Hsp90/AKT signalling pathway in an extracellular signal-regulated kinase-independent manner. The results also provide initial evidence on a molecular basis that SCP-0-1 can be used as an anti-hepatocellular carcinoma therapeutic agent in the future.
Highlights
Liver cancer, called hepatocellular carcinoma (HCC), is one of the most frequently presented carcinoma, and the third-greatest cause of lethal malignancy tumor worldwide
The results provide initial evidence on a molecular basis that S. chinensis polysaccharide-0-1 (SCP-0-1) can be used as an anti-hepatocellular carcinoma therapeutic agent in the future
Treatment with 200 μg/mL SCP-0-1 yielded an apoptotic index of 21.63%, and the proliferation inhibitory rate of the HepG2 cells was approximately 30.13%. These results indicate that the antiproliferative activity of SCP-0-1 is mainly attributable to apoptosis rather than autophagy when the HepG2 cells are treated with 200 μg/mL SCP-0-1, which is in accordance with the morphological analysis and biochemical experiments (Figures 3–5)
Summary
Called hepatocellular carcinoma (HCC), is one of the most frequently presented carcinoma, and the third-greatest cause of lethal malignancy tumor worldwide. The mortality rate of HCC is increasing, and approximately 85% of HCC cases occur in developing countries [1]. The incidence of HCC is second in China, the number of incident cases and deaths continue to increase year by year [2]. HCC is the most common cancer in people aged younger than 60 years and the leading cause of cancer death in Chinese men [3]. Chemotherapy is a common therapeutic strategy after surgery, its application is limited due to its serious adverse effects and growing multidrug resistance in tumour cells. Finding new nontoxic anticancer drugs with fewer side effects is imperative [4]. Some phytochemicals that possess anticancer properties such as suppressing cell proliferation and inducing cell death have recently received considerable attention [5]
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