The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway

Abstract

Introduction: Bone metastasis of breast cancer (BC) is a process in which the disruption of the bone homeostatic microenvironment leads to an increase in osteoclast differentiation. Ailanthus altissima shows an inhibitory effect on osteoclast differentiation. Ailanthone (AIL) refers to a natural compound isolated from Ailanthus altissima, a Chinese herbal medicine, and has effective anti-tumor activity in numerous cell lines. Its impact on bone metastases for BC is yet unclear.Methods: We measured the effect of AIL on MDA-MB-231 cells by wound healing experiments, Transwell and colony formation experiment. Using the Tartrate-resistant Acid Phosphatase (TRAP) staining tests, filamentous (F-actin) staining and bone resorption test to detect the effect of AIL on the osteoclast cell differentiation of the Bone Marrow-derived Macrophages (BMMs), activated by the MDA-MB-231 cell Conditioned Medium (MDA-MB-231 CM) and the Receptor Activator of Nuclear factor-κB Ligand (RANKL),and to explore its possibility Mechanisms. In vivo experiments verified the effect of AIL on bone destruction in breast cancer bone metastasis model mice.Results:In vitro, AIL significantly decrease the proliferation, migration and infiltration abilities of MDA-MB-231 cells at a safe concentration, and also reduced the expression of genes and proteins involved in osteoclast formation in MDA-MB-231 cells. Osteoclast cell differentiation of the BMMs, activated by MDA-MB-231 CM and RANKL, were suppressed by AIL in the concentration-dependent manner. Additionally, it inhibits osteoclast-specific gene and protein expression. It was noted that AIL inhibited the expression of the osteoclast differentiation-related cytokines RANKL and interleukin-1β (IL-1β) that were secreted by the MDA-MB-231 cells after upregulating the Forkhead box protein 3 (FOXP3) expression. Furthermore, AIL also inhibits the expression of the Mitogen-Activated Protein Kinase (MAPK), Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and Nuclear factor-κB Ligand (NF-κB) signaling pathways, which then suppresses the MDA-MB-231CM-induced development of Osteoclasts.Conclusion: Our study shows that AIL blocks osteoclast differentiation in the bone metastasis microenvironment by inhibiting cytokines secreted by BC cells, which may be a potential agent for the treatment of BC and its secondary bone metastasis.

Harder, better, faster, stronger? Retrospective chart review of adverse events of interactions between adaptogens and antidepressant drugs

“…Tribulus terrestris is commercialized with indications to improve sexual and athletic performance ( Stefanescu et al, 2020 ). It has been shown that extracts obtained from this plant exhibit inhibitory effects on CYP3A4 ( Wang et al, 2022 ). We have identified three reports of adverse events associated with the concomitant use of this adaptogen and the antidepressants metabolized by this enzyme.…”

In Vitro Screening of Ecotoxic and Cytotoxic Activities of Ailanthus altissima Leaf Extract against Target and Non-Target Plant and Animal Cells

“…A similar test but on model lipid membranes has also been studied for medicinal and food applications [ 29 , 30 ]. The cytotoxicity of A. altissima against several tumor cells, such as HepG2 [ 31 , 32 ], HeLa [ 31 , 33 ], 786-O [ 31 ], A549 [ 31 , 34 , 35 ], Jurkat [ 36 ], R-HepG2 [ 37 ], MCF-7 [ 34 , 38 ], Hep3B [ 37 ], MDA-MB-231 [ 34 , 39 ], LAPC4, A375, B16 [ 40 ], and SGC-790 [ 41 ], has been reported.…”

Targeting Triple-Negative Breast Cancer by the Phytopolyphenol Carnosol: ROS-Dependent Mechanisms

“…Several phytochemicals have been reported to display anticancer activity against cancer, including TNBC, such as resveratrol, indole-3-carbino, fisetin, 6-gingerol, curcumin, capsaicin, quercetin, ursolic acid, ailanthone, and cordycepin [25][26][27][28][29][30][31]. These phytochemicals reportedly target several molecular pathways implicated in carcinogenesis, including apoptosis, proliferation, inflammation, invasion, metastasis, angiogenesis, and chemoresistance [25][26][27][28][29][30][31].…”

“…Several phytochemicals have been reported to display anticancer activity against cancer, including TNBC, such as resveratrol, indole-3-carbino, fisetin, 6-gingerol, curcumin, capsaicin, quercetin, ursolic acid, ailanthone, and cordycepin [25][26][27][28][29][30][31]. These phytochemicals reportedly target several molecular pathways implicated in carcinogenesis, including apoptosis, proliferation, inflammation, invasion, metastasis, angiogenesis, and chemoresistance [25][26][27][28][29][30][31]. Multiple cellular signaling pathways implicated in tumor development and metastasis, such as TNF-α, Notch, Wnt-β, TGF-β, Ras, EGFR, INF-γ, hedgehog, TLR/NF-kB/NLR, PLK, CCNB1, PI3K/AKT, IL-1β, RANKL, SLUG, TWIST1, SNAIL1, and ZEB1, have been modulated by phytochemicals [28][29][30][31][32].…”

“…These phytochemicals reportedly target several molecular pathways implicated in carcinogenesis, including apoptosis, proliferation, inflammation, invasion, metastasis, angiogenesis, and chemoresistance [25][26][27][28][29][30][31]. Multiple cellular signaling pathways implicated in tumor development and metastasis, such as TNF-α, Notch, Wnt-β, TGF-β, Ras, EGFR, INF-γ, hedgehog, TLR/NF-kB/NLR, PLK, CCNB1, PI3K/AKT, IL-1β, RANKL, SLUG, TWIST1, SNAIL1, and ZEB1, have been modulated by phytochemicals [28][29][30][31][32].…”