Icariin Synergizes with Arsenic Trioxide to Suppress Human Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is an aggressive malignancy with high chemoresistance to chemotherapeutics. Arsenic trioxide (ATO) is of therapeutic potential for the treatment of HCC; however, the therapeutic benefit of ATO is very limited due to narrow therapeutic window. Icariin is a natural compound which inhibits tumour cell growth and induces apoptotic cell death in a variety of cancer cells. This study was designed to determine whether Icariin can potentiate the antitumour activity of ATO in HCC treatment. Cell proliferation and apoptosis were measured using an MTT assay and flow cytometry respectively. Changes in reactive oxygen species (ROS) level and mitochondrial membrane potential were analysed by fluorescence signals. Protein expression was measured by western blotting and NF-κB activity was determined by ELISA assay. In addition, the antitumour effect of combination treatment with Icariin and ATO on HCC was evaluated using a murine HCC cancer xenograft model. Icariin inhibited proliferation and induced apoptosis in both of the tested HCC cell lines in a dose-dependent fashion. Icariin enhanced the antitumour activity of ATO both in vitro and in vivo. The antitumour activity of Icariin and its enhancement of the antitumour activity of ATO correlated with the generation of intracellular ROS and inhibition of NF-κB activity. Our results showed that Icariin potentiated the antitumour activity of ATO in HCC. Therefore, we propose that the combination treatment with Icariin and ATO might facilitate the optimization of ATO therapy for patients with HCC.

Activation of endoplasmic reticulum stress is involved in the activity of icariin against human lung adenocarcinoma cells

“…As a natural prenylated flavonol glycoside, ICA has been shown to suppress the proliferation of various types of cancer cells [11][12][13][14]. Various molecules and signaling pathways are involved in the anti-tumor effects of ICA.…”

“…1a) is a prenylated flavonol glycoside derived from the medical plant Herba Epimedii, which is well known for various pharmacological activities [4][5][6][7][8][9][10]. Many studies has been shown that ICA has potent antitumor activities in various cancer types, including breast cancer, human burkitt lymphoma and liver cancer [11][12][13]. Recently, Zhang et al have reported that ICA protected rat cardiac H9c2 cells from apoptosis by inhibiting ERS [14], indicating that ICA might be a cancer-fighting agent through the regulation of the ERS.…”

Cotylenin A and arsenic trioxide cooperatively suppress cell proliferation and cell invasion activity in human breast cancer cells

“…However, it was reported that many solid tumors are less sensitive to ATO than APL. The requirement of higher doses of ATO for the induction of effective growth inhibition of solid tumor cells was associated with the risk of severe adverse effects such as leukopenia, anemia, fever and vomiting (14)(15)(16)37). Combination therapy is a frequently used method in clinical practice to improve the therapeutic effect and reduce the toxicity of anticancer drugs (17,18).…”

Arsenic Trioxide Inhibits Proliferation of Rabbit Tenon's Capsule Fibroblasts After Trabeculectomy by Downregulating Expression of Extracellular Matrix Proteins

“…15 Recently, arsenic trioxide has been found to induce cancer cell apoptosis and inhibit cancer cell migration and invasion through suppressing matrix metalloproteinase (MMP)-2 and MMP-9 expression in solid tumors. 16 In the current study, we aimed to investigate if arsenic trioxide mediated suppression of rabbit TFs proliferation involves the downregulation of the expression of ECM proteins after trabeculectomy in an animal model. covered with Dulbecco's modified Eagle's medium/Ham's nutrient mixture F12 medium (DMEM F12; Gibco BRL, Gaithersburg, MD, USA) supplemented with 50 ng streptomycin and 500000 U/L penicillin (Gibco Ltd., Uxbridge, UK).…”

“…In fact the cell proliferation inhibition, which appeared to be in a dose-dependent manner was assessed as described previously. 15,16 Western Blotting Assay Total protein from rTFs cultured in the serum-free medium containing 0.5 mg/mL BSA (HyClone Labs, Logan, UT, USA) was extracted after their treatment with or without arsenic trioxide. Next, the protein concentration was determined using Bradford chromometry and the total protein was separated by 10% SDS-PAGE.…”