Huaier polysaccharide induces apoptosis in hepatocellular carcinoma cells through p38 MAPK

Abstract

Abstract. The underlying mechanism of the antitumor activity of Huaier polysaccharide (HP) remains to be explored. The present study aimed to investigate the inhibitory effect of HP on hepatocellular carcinoma (HCC) cells, and to explore the possible mechanisms of its anticancer effect. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, while apoptotic nuclear changes were observed using Hoechst 33258 staining. The distribution of cell cycle and apoptosis were analyzed by flow cytometry, and western blotting was used to test the apoptotic pathways. Apoptosis and mitogen-activated protein kinase (MAPK) inhibitors were used to investigate the mechanism of apoptosis. HP triggered cell cycle arrest and apoptosis in HepG2 and Huh7 cells. Both the extrinsic and intrinsic apoptotic pathways were activated after HP treatment. Furthermore, HP enhanced the three major MAPK pathways (extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38 MAPK) and inhibited the AKT/mechanistic target of rapamycin signaling pathway in HCC cells. Notably, the inactivation of p38 MAPK impaired the HP-induced cell death. HP exerted its antitumor effect on HCC cells through the regulation of the expression of the apoptosis-related proteins B-cell lymphoma (Bcl)-2, Bcl-2-associated X protein and survivin. The present study provides evidence that HP induces apoptosis in HCC cells and demonstrated the role of p38 MAPK in HP-triggered cancer cell death. IntroductionLiver cancer, particularly hepatocellular carcinoma (HCC), is one of the most common human malignancies with poor long-term survival rates (1-3). Although liver transplantation, hepatectomy and local therapy are potentially curative therapies in the early stages of HCC (4,5), the majority of patients, who are usually diagnosed at an advanced stage, must rely mainly on traditional chemotherapies (6,7). Currently, there is no proven effective conventional systemic chemotherapy for patients with advanced HCC (7). Therefore, novel therapeutic agents with high efficacy are urgently required for the clinical treatment of advanced HCC.Trametes robiniophila Murr (Huaier) is a type of fungus that exists in China, and previous chemical analyses revealed that Huaier consists mainly of polysaccharide (8). Recent studies have noticed that Huaier polysaccharide (HP) exerts a pro-apoptotic effect on the cells of a variety of human cancers, including breast cancer (9,10), hepatocarcinoma (11-14), lung adenocarcinoma (15) and ovarian cancer (16). In addition, Huaier and HP suppress cancer cell metastasis and motility (12,16,17), exhibit anti-angiogenic activity and enhance the host immune system function (11,14,18). Together, these data indicate that HP exhibits promising results against cancer in pre-clinical trials.The use of Huaier has been approved by the Chinese Food and Drug Administration for the clinical treatment of patients with malignant tumors (China Food and Drug Administration approval number, Z20000109; http://app1.sfda.gov.cn...

A novel chemoprotective effect of tiopronin against diethylnitrosamine‐induced hepatocellular carcinoma in rats: Role of ASK1/P38 MAPK‐P53 signalling cascade

“…However, our results are in contrast with previous studies showing that activation of the ASK1‐p38 MAPK signalling cascade induces apoptosis in many HCC cell lines . Additionally, Bao et al reported that p38 MAPK induces apoptosis in HepG2 and Huh7 cells through upregulation of apoptosis‐related proteins, including p53, caspases and Bcl‐2 proteins …”

Huaier extract enhances the treatment efficacy of paclitaxel in breast cancer cells via the NF-κB/IκBα pathway

“…Huaier extract has been found to not only have an antitumor effect, but also enhance the sensitivity of cancer cells to chemotherapy drugs and improve immunity and long-term prognosis in cancer patients (29,30). Bao et al (18) found that the Huaier extract inhibited the proliferation of human hepatocellular carcinoma Hep-G2 cells and induced cell apoptosis in a concentration-dependent manner. In the present study, after treating MCF-7 and MDA-MB-231 cells with Huaier extract for 24 and 48 h, we found that Huaier extract inhibited cell proliferation, reduced cell viability and promoted cell apoptosis in a time-and dose-dependent manner, results which were consistent with a study from Zhang et al (14).…”

“…It has been demonstrated that the main anticancer mechanisms of Huaier are achieved by inhibiting the growth and proliferation of cancer cells, inducing apoptosis, decreasing drug resistance in cancer cells, and improving immunity as well (16,17). In vitro experiments revealed that Huaier extract inhibited the growth of hepatocarcinoma and human lung adenocarcinoma cells (18,19). Huaier extract could inhibit the growth of ERα-positive breast cancer cells through the ERα/NF-κB pathway (20).…”

TXNIP overexpression suppresses proliferation and induces apoptosis in SMMC7221 cells through ROS generation and MAPK pathway activation

“…Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and causes approximately 600,000 deaths every year (1,2). Although liver transplantation and surgical resection are the most efficient therapeutic strategies for early stage HCC (3,4), the majority of patients, who are usually diagnosed at an advanced stage, must rely on traditional chemotherapies (5).…”

“…Thioredoxin interaction protein (TXNIP) is a 46 kDa protein that was first identified in an HL-60 leukemia cell line treated with 1α, 25-dihydroxyvitamin D 3 [1,25(OH 2 ) D 3 ] (11). As a negative regulator of thioredoxin (TRX), TXNIP was found to be an inducer of the intracellular level of reactive oxygen species (ROS) (12).…”