Abstract
Dihydroartemisinin (DHA) and artesunate (ARS), two artemisinin derivatives, have efficacious anticancer activities against human hepatocarcinoma (HCC) cells. This study aims to study the anticancer action of the combination treatment of DHA/ARS and farnesylthiosalicylic acid (FTS), a Ras inhibitor, in HCC cells (Huh-7 and HepG2 cell lines). FTS pretreatment significantly enhanced DHA/ARS-induced phosphatidylserine (PS) externalization, Bak/Bax activation, mitochondrial membrane depolarization, cytochrome c release, and caspase-8 and -9 activations, characteristics of the extrinsic and intrinsic apoptosis. Pretreatment with Z-IETD-FMK (caspase-8 inhibitor) potently prevented the cytotoxicity of the combination treatment of DHA/ARS and FTS, and pretreatment with Z-VAD-FMK (pan-caspase inhibitor) significantly inhibited the loss of ΔΨm induced by DHA/ARS treatment or the combination treatment of DHA/ARS and FTS in HCC cells. Furthermore, silencing Bak/Bax modestly but significantly inhibited the cytotoxicity of the combination treatment of DHA/ARS and FTS. Interestingly, pretreatment with an antioxidant N-Acetyle-Cysteine (NAC) significantly prevented the cytotoxicity of the combination treatment of DHA and FTS instead of the combination treatment of ARS and FTS, suggesting that reactive oxygen species (ROS) played a key role in the anticancer action of the combination treatment of DHA and FTS. Similar to FTS, DHA/ARS also significantly prevented Ras activation. Collectively, our data demonstrate that FTS potently sensitizes Huh-7 and HepG2 cells to artemisinin derivatives via accelerating the extrinsic and intrinsic apoptotic pathways.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancers and the second most lethal cancer worldwide [1,2]
This report for the first time assessed the effect of farnesylthiosalicylic acid (FTS) on the cytotoxicity of DHA/ARS in HCC cells
Our results showed that FTS significantly sensitized HCC cells to DHA/ARS by enhancing the extrinsic and the intrinsic apoptotic pathways, exhibiting a synergistic anticancer effect
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancers and the second most lethal cancer worldwide [1,2]. Several approaches are available for HCC therapy including surgical resection, liver transplantation, chemotherapy and radiotherapy [3,4,5,6,7]. FTS sensitizes HCC cells to ARTs. Surgical resection and liver transplantation are two main curative treatments for patients with early HCC [2]. Only a minority of the patients can be offered a curative treatment because most patients are often diagnosed at advanced stages of HCC [5]. High resistance of HCC to available chemotherapeutic agents and the low tolerance of the liver to irradiation result in the limitation of chemotherapy and radiotherapy [1]. Discovery and development of innovative anti-HCC agents with lower host toxicity has turned to natural sources and their combined treatment with other drugs [8,9,10,11,12,13,14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
