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

Abstract

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.

Integrated metabolomics, network pharmacology and biological verification to reveal the mechanisms of Nauclea officinalis treatment of LPS-induced acute lung injury

“…Moreover, LA produces arachidonic acid (AA), which can produce prostaglandins (PGs) and leukotrienes (LTs) under the action of cyclooxygenase (COX). Studies have shown that increasing LA intake may decrease the risk of pneumonia [ 32 ]. Moreover, AA has activity against bacteria, fungi, and influenza viruses, whereas alveolar macrophages can release AA and other unsaturated fatty acids into alveolar fluid, thereby exerting their antibacterial impact and protecting the lungs from various microbial infections [ 33 ].…”

Meta-analysis of the efficacy and safety of Xihuang Pills/capsules in adjuvant treatment of uterine cervical neoplasms

“…Additionally, the experimental group showed better post-treatment levels (CD3 + CD4+, MD = 7.06, 95% CI: 3.56-10.57, P < .0001; CD3 + CD8+, MD = 5.49, 95% CI: 2.30-8.69, P = .0008; CD3 − CD56+, MD = 4.99, 95% CI: 2.07-7.91, P = .0008), and there was no significant heterogeneity (CD3 + CD4+, χ 2 = 0.16, P = .69, I 2 = 0%; CD3 + CD8+, χ 2 = 0.74, P = .39, I 2 = 0%; CD3 − CD56+, χ 2 = 0.16, P = .69, I 2 = 0%) (Figs. [20][21][22]. Moreover, patients treated with Xihuang Pills/Capsules in combination with Western medicine had higher immunoglobulin M levels (MD = 0.52, 95% CI: 0.11-0.93, P = .01, 2 studies, 158 patients).…”

“…Today, Xihuang Pills/Capsules find extensive application in clinical research as adjuvant therapy for various malignant tumors, including breast cancer, colorectal cancer, ovarian cancer, lung cancer, liver cancer, and lymphoma. [17][18][19][20][21][22] However, there is currently a lack of evidence-based medical studies on uterine cervical neoplasms. Consequently, to assess the clinical safety of Xihuang Pills/ Capsules when combined with other therapies for treating cervical neoplasms, this study conducted a meta-analysis of randomized controlled trials (RCTs).…”

Metabolomics Combined with Network Pharmacology-Based Strategy to Reveal the Underlying Mechanism of Zhenhuang Submicron Emulsion in Treating Oropharyngeal Mucositis Complications of Radiation Therapy for Head and Neck Cancer

“…9 These diseases include but are not limited to coronary heart disease, 10 type 2 diabetes mellitus, 11 metabolic diseases, 12 traumatic brain injury, 13 Alzheimer's disease 14 and lung cancer. [15][16][17] Network pharmacology is also increasingly applied in the research of traditional Chinese medicine. 18 Abundant information including bioactive compounds, targets, and the interactions between these can be obtained by constructing a network pharmacology model.…”