An Integrative Metabolomic and Network Pharmacology Study Revealing the Regulating Properties of Xihuang Pill That Improves Anlotinib Effects in Lung Cancer

Frontiers in Oncology

Mingyu Zhang¹  Qiong Gu¹  Shuya Qi¹  Xiaofei Fei¹  Zhihong Wang¹  Guohui Li¹  Chunyu Li¹  Bo Cao¹  Wei Chen¹  Yafei Shi¹  Xingjie Li²  RuiSheng Li²  Jiabo Wang³ 

[1] National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;Research Center for Clinical and Translational Medicine, Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China;School of Traditional Chinese Medicine, Capital Medical University, Beijing, China;

关键词: Xihuang pill;    anlotinib;    lung cancer;    untargeted metabolomics;    network pharmacology;    integrated strategy;   

DOI  :  10.3389/fonc.2021.697247

来源: DOAJ

【 摘 要 】

Lung cancer ranks as a leading cause of death. Although targeted therapies usually trigger profound initial patient responses, these effects are transient due to drug resistance and severe side effects. Xihuang Pill (XHW) is a popular Chinese medicine formula that might benefit cancer patients when used as a complementary therapy. However, its underlying mechanism when combined with anticancer drugs is not clearly understood. Here, we used an integrated strategy to reveal the regulatory properties of XHW in increasing the antitumor activity of anlotinib in lung cancer. We evaluated the anti-lung cancer effect of XHW combined with anlotinib in mice bearing Lewis lung carcinoma (LLC). We applied untargeted metabolomics to identify the differences metabolism and found that XHW improved the effects of anlotinib on lung cancer. The components and targets related to the effects of XHW treatment on lung cancer were obtained through network pharmacology. Then, by integrating the biologically active components of XHW and anlotinib as well as the treatment-responsive metabolites and their related targets, an interaction network was constructed to evaluate the combination therapy. Finally, important protein candidates for this response were verified by immunohistochemistry of tumor tissues. The results showed that XHW significantly improved the inhibitory effect of anlotinib on tumor growth in LLC-bearing mice. Additionally, 12 differentially-abundant metabolites were identified by untargeted metabolomics in the XHW/anlotinib group compared with the XHW or anlotinib groups, and they were mainly enriched in fatty acid metabolism, lipid metabolism and amino acid metabolism pathways. Anlotinib, 23 components in Shexiang, 2 components in Niuhuang, 30 components in Ruxiang and 60 components in Moyao work together to act on 30 targets to regulate hexadecanoic acid (also named palmitic acid), linoleic acid, lactosylceramide, adrenaline, arachidonic acid and lysoPC(18:1(9Z)). The results of immunohistochemistry showed that XHW combined with anlotinib reduced the expression of PDGFRA in tumors. Overall, the key metabolites of XHW that enhances the efficacy of anlotinib were regulated by a multicomponent and multitarget interaction network. Our results suggested that anlotinib combined with XHW may be a promising strategy for the treatment of lung cancer.

【 授权许可】

Unknown