Identification of the anti-breast cancer targets of triterpenoids in Liquidambaris Fructus and the hints for its traditional applications

Abstract

Background Liquidambaris Fructus is the infructescences of Liquidambar formosana Hance and it has been used to treat some breast disease in Traditional Chinese Medicine. In the previous study we found the anti-breast cancer effect of triterpenoid in Liquidambaris Fructus. This study is a further investigation of the triterpenoids in Liquidambaris Fructus and aims to identify their anti-breast cancer targets, meanwhile, to estimate the rationality of the traditional applications of Liquidambaris Fructus. Methods Triterpenoids in Liquidambaris Fructus were isolated and their structures were identified by NMR spectrums. Potential targets of these triterpenoids were predicted using a reverse pharmacophore mapping strategy. Associations between these targets and the therapeutic targets of breast cancer were analyzed by constructing protein-protein interaction network, and targets played important roles in the network were identified using Molecular Complex Detection method. Binding affinity between the targets and triterpenoids was studied using molecular docking method. Gene ontology enrichment analysis was conducted to reveal the biological process and signaling pathways that the identified targets were involved in. Results Thirteen triterpenoids were identified and 6 of them were the first time isolated from Liquidambaris Fructus. Predicted ADME properties revealed a good druggability of these triterpenoids. We identified 18 protein targets which were closely related to breast cancer progression, especially triple-negative, basal-like or advanced stage breast cancers. The triterpenoids could bind with these targets as their inhibitors: hydrophobic skeleton is a favorable factor for them to stabilize at binding site and polar C17- or C3- substituent was necessary for binding. GO enrichment analysis indicated that inhibition of protein tyrosine kinases autophosphorylation might be the primary mechanism for the anti-breast cancer effect of the triterpenoids, and ErbB4 and EGFR were the most relevant targets. Conclusions The study revealed that triterpenoids from Liquidambaris Fructus might exert anti-breast cancer effect by directly inhibit multiple protein targets and signaling pathways, especially ErbB4 and EGFR and related pathways. This study also brings up another hint that the traditional applications of Liquidambaris Fructus on hypogalactia should be reassessed systematically because it might suppress rather than promote lactation by inhibiting the activity of ErbB4.

Betulin, a Newly Characterized Compound in Acacia auriculiformis Bark, Is a Multi-Target Protein Kinase Inhibitor

“…The inhibition of the ABL1 activity by 10 µM betulin was significantly decreased in the presence of a high concentration of ATP (100 µM). We note here that other triterpenoids, for example those extracted from the dry infructescences of Liquidambaris Fructus (also called Lu Lu Tong when used in Traditional Chinese medicine to treat some breast disease) have also been implicated as putative ATP competitors [ 26 ].…”

Integrated Strategy of UHPLC-Q-TOF-MS and Molecular Networking for Identification of Diterpenoids from Euphorbia fischeriana Steud. and Prediction of the Anti-Breast-Cancer Mechanism by the Network Pharmacological Method

“…MAPK may increase the phosphorylation of cyclins and promote the progression through cell cycle. The MAPK pathways interact with the phosphorylation level and states of ER and PGR [ 61 ]. Progestin can activate c-SRC and enhance prolactin-mediated activation of STAT through MAPK pathways to promote cell proliferation [ 62 , 63 ].…”

Immunomodulatory activity of Pepolo (Bischofia javanica Blume) stem bark ethanolic extract in Staphylococcus aureus-stimulated macrophages and anticancer activity against MCF-7 cancer cells

“…Also, stigmastans can induce a T-helper cell response with immunomodulatory properties (Yuliastri et al, 2021). Ambronal inhibition of protein tyrosine kinase autophosphorylation might be the primary mechanism for the anticancer effect (Qian et al, 2020). The activity can result from the synergistic effect of the compounds.…”