Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells

Abstract

BackgroundErgosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells.ResultsDespite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control.ConclusionThese findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells.

Logic-Based and Cellular Pharmacodynamic Modeling of Bortezomib Responses in U266 Human Myeloma Cells

“…Natural cell growth and death were modeled using first-order growth rate constants (k g and k d ). The estimated net growth rate constant (k g -k d ) in the final model (0.00490 h 21 ) is comparable to net growth rate constants from U266 xenografts at 0.00487 h 21 (Siveen et al, 2014) and 0.00450 h 21 (Rhee et al, 2012) that were obtained by fitting an exponential model to digitized control curves (data not shown).…”

Natural Bioactive Sterol 5α,8α-endoperoxides as Drug Lead Compounds

“…In a number of cases their chemical synthesis appears more convenient, especially if the initial ∆ 5,7 -or ∆ 5,7,9(11) -sterols are available. This is also favored by the circumstance that chemical synthesis of 5,8-epidioxides are based on the well-studied photochemical oxidation of 5,7-diene group in sterols (Figure 10).…”

“…In ethanol, the expected 1 and main products (22E)-ergosta-5,7,9,22-tetraen-3β-ol (DHE) and by-product (22E)-5α,8α-epidioxyergosta-6,9,22-trien-3β-ol (EEP9 (11)), (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (DHOE) were obtained. In methyl tert-butyl ether, a complex mixture of 1, KE, DHOE, EEP9 (11) In cases where the initial ∆ 5,7 -sterols are unavailable, special schemes of synthesis must be developed for obtaining the 5,8-epidioxides. The synthesis of endoperoxide 3 started from cholesterol, cholesterol was converted to cholesterol-3-acetate to protect the hydroxy group [40].…”

“…A number of biological activities have been attributed to ergosterol peroxide, such as anti-tumor activity, immunomodulatory activity, inhibitory hemolytic activity and anti-inflammatory activity, antiviral activity et al Ergosterol peroxide has shown to exert anti-tumor activity in multiple myeloma U266 cells partly with anti angiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells [5]. Ergosterol peroxide is also against Walker carcinosarcoma and human mammary adenocarcinoma cell lines in vitro, as well as against human gastric tumor cell line (SNU-1), human hepatoma cell line (SUN-354), human colorectal tumor cell line (SUN-C4), and murine sarcoma-180.…”

Triterpenes from Poria cocos suppress growth and invasiveness of pancreatic cancer cells through the downregulation of MMP-7

“…As one of the most aggressive human cancers, the 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is <5% (1). Recent studies suggested that bioactive compounds from mushrooms could protect against multiple myeloma, breast and skin cancer (2)(3)(4)(5). Poria cocos (also known as Wolfiporia extensa) is a medicinal mushroom in the Polyporaceae family that grows in pine trees and its sclerotium is widely used in traditional Asian medicine for its sedative, diuretic, digestive and tonic effects (6)(7)(8).…”