Abstract
Ursolic acid (UA) is a pentacyclic triterpene acid that is present in a wide variety of medicinal herbs and edible plants. This study investigated the effect of UA on apoptosis and proliferation of hepatocellular carcinoma SK-Hep-1 cells. After treatment of SK-Hep-1 cells with different concentrations of UA, we observed that cell viability was reduced in a dose- and time-dependent manner. Furthermore, there was a dose-dependent increase in the percentage of cells in the sub-G1 and G2/M phases, with cells treated with 60 μM showing the highest percentages of cells in those phases. UA-induced chromatin condensation of nuclei was observed by using DAPI staining. The western blot results revealed that exposure to UA was associated with decreased expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, Bcl-2, and TCTP and increased expression of apoptosis-related proteins TNF-α, Fas, FADD, Bax, cleaved caspase-3, caspase-8, caspase-9, and PARP. Immunocytochemistry staining showed that treatment with UA resulted in increased expression of caspase-3. Moreover, exposure to UA resulted in the inhibition of the PI3K/Akt and p38 MAPK signaling pathways. These findings suggest that UA inhibits the proliferation of SK-Hep-1 cells and induces apoptosis.
Highlights
We examined the effect of Ursolic acid (UA) on apoptosis and cell proliferation in the human novel drugs target for inducing apoptosis in cancer cells could contribute to the development of new hepatocellular carcinoma line SK-Hep-1
We found that treatment with UA inhibits the hepatocellular proliferation of SK-Hep-1 cells and induces apoptosis by inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt and p38 mitogen-activated protein kinase (MAPK)
SK-Hep-1 cells were treated with various concentrations (0, 20, 40, and 60 μM) of UA for 24 h and and the relative expression of apoptosis-related proteins was evaluated by western blotting
Summary
Ursolic acid (UA, 3β-hydroxyurs-12-en-28-oic acid, Figure 1) is a pentacyclic triterpenoid carboxylic acid found in abundance in a number of plants and medicinal herbs such as apples [1], basil, bilberries, cranberries, lavender, rosemary (Rosmarinus officinalis L.) [2], sage (Slavia officinalis L.) [3], snake-needle grass (Oldenlandia diffusa) [4] and Jamun plum (Eugenia jumbolana) [5].Studies have demonstrated that UA has a number of pharmacological effects including anti-inflammatory, anti-oxidative [6], antibacterial, antifungal [7], anti-mutagenic, antiangiogenic [8], anti-viral, anticarcinogenic [9], hepatoprotective [10], anti-atherosclerotic anti-tumor [11] and anti-hyperlipidemic activity. UA has been shown to induce apoptosis in a number of human cancer cell lines [5,12,13,14,15,16,17,18,19,20]. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is the second leading cause of cancer death worldwide [21]. According to BCLC staging system, the treatment methods for HCC were different depending on staging [22]. Numerous treatment methods have been suggested for HCC management, such as surgical resection and liver transplantation, Molecules 2016, 21, 460; doi:10.3390/molecules21040460 www.mdpi.com/journal/molecules the the5-year
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