A novel component from citrus, ginger, and mushroom family exhibits antitumor activity on human meningioma cells through suppressing the Wnt/β-catenin signaling pathway

Abstract

Recurrent meningiomas constitute an uncommon but significant problem after standard (surgery and radiation) therapy failure. Current chemotherapies (hydroxyurea, RU-486, and interferon-α) are only of marginal benefit. There is an urgent need for more effective treatments for meningioma patients who have failed surgery and radiation therapy. Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM are some of the plant derivatives that have anti-tumorgenic properties and cause cell death in meningioma cells in vitro. Due to its ease of administration, long-term tolerability, and low incidence of long-term side effects, we explored its potential as a therapeutic agent against meningiomas by examining their efficacy in vitro against meningioma cells. Treatment effects were assessed using MTT assay, Western blot analysis, caspases assay, and DNA fragmentation assay. Results indicated that treatments of IOMM-Lee and CH157MN meningioma cells with Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM induced apoptosis with enhanced phosphorylation of glycogen synthase kinase 3 β (GSK3β) via inhibition of the Wnt5/β-catenin pathway. These drugs did not induce apoptosis in normal human neurons. Other events in apoptosis included downregulation of tetraspanin protein (TSPAN12), survival proteins (Bcl-XL and Mcl-1), and overexpression apoptotic factors (Bax and caspase-3). These results provide preliminary strong evidence that medicinal plants containing Limonin, Tangeritin, 6-Gingerol, Zerumbone, Ganoderic Acid A, and Ganoderic Acid DM can be applied to high-grade meningiomas as a therapeutic agent, and suggests that further in vivo studies are necessary to explore its potential as a therapeutic agent against malignant meningiomas.

The Chemistry and Pharmacology of Citrus Limonoids

“…The unbalanced solubility profile of the latter may explain the relatively low number of studies on their respective biological activities which are hampered by difficult isolation from natural sources and poor pharmacokinetics. Analgesic [45], anticancer [46][47][48][49][50][51][52][53][54][55][56][57][58][59], anti-inflammatory [45,[60][61][62], antibacterial [63,64], antioxidant [4,65,66], antiviral [67], larvicidal [68,69] Anticancer [46,47,58,59,70], anti-hyperglycemic [71], anti-inflammatory [25,62], antioxidant [4,65,66], antiviral [67], larvicidal [68,69] …”

“…Limonin (1) was also found in this study to downregulate the expression of LRP5, LRP6, and DKK wnt players, which forms a rationale for further investigation on effect of 1 cancer therapy. Das et al [56] further showed that the treatments of IOMM-Lee and CH157MN meningioma cells with (1) can induce apoptosis with enhanced phosphorylation of glycogen synthase kinase 3 β (GSK3β) via inhibition of the Wnt5/β-catenin pathway (EC 50 = 25 µM). While studying the effects of 1 on intestinal polyp from Apc-mutant Min mice, Shimizu et al [54] have observed a reduction of neoplastic cell proliferation after treatment with 1, along with reduced level of expression of c-Myc and MCP-1 mRNA in the polyp part.…”

Ganoderic Acid A Metabolites and Their Metabolic Kinetics

“…In a previous study, GAA was chosen as the single reference substance for multiple components determination for quantity control of GL (Da et al, 2015). GAA reportedly exhibited antinociceptive (Koyama et al, 1997), antioxidative (Zhu et al, 1999), cytotoxic (Guan et al, 2008) and hepatoprotective activities (Kim et al, 1999), especially anticancer activity (Jiang et al, 2008; Yao et al, 2012; Das et al, 2015; Radwan et al, 2015; Shao et al, 2015), which is the most attractive character of this compound.…”

“…Recent studies showed that GAA exhibits antitumor activity on human osteosarcoma (Shao et al, 2015), lymphoma (Radwan et al, 2015), meningioma (Das et al, 2015) and breast cancer cells (Jiang et al, 2008) through suppressing growth and invasive behavior and/or inducing apoptosis of cancer cells. GAA could also enhance chemosensitivity of HepG2 cells to Cisplatin (Yao et al, 2012).…”

Anti‑angiogenic and anti‑proliferative effects of Benja‑ummarit extract in rats with hepatocellular carcinoma

“…Aloe-emodin in aloe vera, 6-gingerol in ginger and piperine in black pepper are all reported to inhibit tumor invasion and metastasis through the suppression of expression of matrix metalloproteinase-2/9 (38,42). All ingredients of BU, except epsom salts, have been revealed to exert apoptotic activity in various cancer cell lines, including SMMC-7721 (56), a human glioblastoma cell line (U87MG) (57), prostate cancer (58), H460 non-small cell lung carcinoma (59), adriamycin-resistant human leukemia (K562/ADR) (60), MCF-7 (61), IOMM-Lee and CH157MN (62) via the overexpression of BCL2 associated X, apoptosis regulator (60)(61)(62), caspase 3 (57,62), caspase 8 (57), caspase 9 (59), induced ROS accumulation (56,61) or via the AKT/mitogen-activated protein kinase pathway (60).…”