The Synergistic Antitumor Effect of Tanshinone IIA Plus Adriamycin on Human Hepatocellular Carcinoma Xenograft in BALB/C Nude Mice and Their Influences on Cytochrome P450 CYP3A4 In Vivo

Tao-Li Liu; Li-Na Zhang; Yue-Yu Gu; Mei-Gui Lin; Jun Xie; Yu-Ling Chen; Jia-Hui Liu; Xin-Lin Wu; Sui-Lin Mo

doi:10.1155/2020/6231751

The Synergistic Antitumor Effect of Tanshinone IIA Plus Adriamycin on Human Hepatocellular Carcinoma Xenograft in BALB/C Nude Mice and Their Influences on Cytochrome P450 CYP3A4 In Vivo

Adv Med. 2020 Feb 29:2020:6231751. doi: 10.1155/2020/6231751. eCollection 2020.

Authors

Tao-Li Liu¹, Li-Na Zhang², Yue-Yu Gu³, Mei-Gui Lin⁴, Jun Xie⁵, Yu-Ling Chen⁶, Jia-Hui Liu⁷, Xin-Lin Wu⁷, Sui-Lin Mo⁷

Affiliations

¹ The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China.
² The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China.
³ The Second Clinical College, Guangzhou University of Chinese Medicine and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510080, China.
⁴ Li Wan District Shi Wei Tang Street Community Health Service Center, Guangzhou 510360, China.
⁵ Peking Union Medical College Hospital, Peking Union Medical College, China Academy of Medical Sciences, Beijing 100730, China.
⁶ Sydney Acupuncture & Chinese Medicine Centre, New South Wales 2220, Australia.
⁷ The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.

Abstract

Objective: Hepatocellular carcinoma is one of the most common diseases that seriously threaten human life and health. In this study, we evaluated the inhibitory effect of tanshinone IIA (Tan IIA) combined with adriamycin (ADM) on human hepatocellular carcinoma and developed a platform to assess the function if Chinese herbal ingredients combined with chemotherapy drugs have synergistic antitumor effects in vivo.

Methods: Established animal model of human hepatocarcinoma HepG2 cell in nude mice. Mice were divided into model control group, Tan IIA group, ADM group, and Tan IIA + ADM group. The changes from general condition, weight, tumor volume, and inhibition rate were observed. The data were gathered from serum AST level and histopathological changes. The content and activity of cytochrome P450 were determined by spectrophotometric analysis. CYP3A4 protein expression was analyzed by western blotting. The binding model crystal structure of Tan IIA and ADM with pregnane X receptor (PXR) was evaluated by Discovery Studio 2.1.

Results: A combination of Tan IIA with ADM could improve life quality by relieving ADM toxicity, decreasing tumor volume, declining serum AST level, and improving liner pathological section in tumor-bearing mice. The inhibitory rates of Tan IIA, ADM, and cotreatment were 32.77%, 60.96%, and 73.18%, respectively. The Tan IIA group significantly enhanced the content of cytochrome b5, P450, and erythromycin-N-demethylase activity. CYP3A4 protein expression was enhanced obviously by the Tan IIA + ADM group. Virtual molecular docking showed that both Tan IIA and ADM could be stably docked with the same binding site of PXR but different interactions.

Conclusions: Tan IIA in combination with ADM could improve the life quality in tumor-bearing mice and enhance the antitumor effect. The Tan IIA group increased the concentration of cytochrome P450 enzymes and activity. Combined Tan IIA with ADM could upregulate the CYP3A4 protein expression and make relevant interaction with protein PXR by virtual docking.