Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation

Feng,Xu‑Qin; Rong,Li‑Wen; Wang,Rui‑Xue; Zheng,Xue‑Lian; Zhang,Lei; Zhang,Lin; Lin,Yong; Wang,Xia; Li,Zhi‑Ping

doi:10.3892/ol.2018.8640

Luteolin and sorafenib combination kills human hepatocellular carcinoma cells through apoptosis potentiation and JNK activation

Authors:
- Xu‑Qin Feng
- Li‑Wen Rong
- Rui‑Xue Wang
- Xue‑Lian Zheng
- Lei Zhang
- Lin Zhang
- Yong Lin
- Xia Wang
- Zhi‑Ping Li
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Affiliations: Department of Abdomen Oncology, Cancer Center of West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Laboratory of Molecular and Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) of Ministry of Education, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: May 4, 2018 https://doi.org/10.3892/ol.2018.8640
Pages: 648-653

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Abstract

Sorafenib is a small‑molecule multi‑kinase inhibitor approved by FDA as an oral agent for the treatment of hepatocellular carcinoma (HCC) and renal cell carcinoma. However, unresponsiveness and acquired resistance are commonly observed, which hinder the clinical use of sorafenib. As combination therapy is a promising approach to improve its efficacy, we investigated if sorafenib and luteolin combination is effective in killing human HCC cells. Cell death was examined by lactate dehydrogenase (LDH) releasing assay. Apoptosis was detected by flow cytometric. The activation of apoptotic pathway and c‑Jun N‑terminal kinase (JNK) signaling pathway was measured by western blot. The results showed that sorafenib and luteolin combination synergistically induced cytotoxicity in HCC cells, which was accompanied by potentiation of apoptosis as demonstrated by increased apoptotic cell populations, caspase activation, and suppression of cell death by the pan‑caspase inhibitor z‑VAD‑fmk. Furthermore, the combination of both agents enhanced expression of phosphorylated form of JNK, and the JNK inhibitor SP600125 effectively attenuated cell death induced by the combination treatment. Thus, sorafenib and luteolin combination synergistically kills HCC cells through JNK‑mediated apoptosis, and luteolin may be an ideal candidate for increasing the activity of sorafenib in HCC therapy.

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