Abstract
Malignant gliomas are the most aggressive forms of brain tumors; whose metastasis and recurrence contribute to high rates of morbidity and mortality. Glioma stem cell-like cells are a subpopulation of tumor-initiating cells responsible for glioma tumorigenesis, metastasis, recurrence and resistance to therapy. Epidermal growth factor receptor (EGFR) has been reported to be dysregulated in most cancers, including gliomas and its functions are closely linked to initiating tumor metastasis and a very poor prognosis. In search for compounds that may reduce the tumorigenic potential of gliomas/glioblastomas honokiol attracted our attention. Honokiol, purified from the bark of traditional Chinese herbal medicine Magnolia species, is beneficial in vitro and in animal models via a variety of pharmacological effects, including anti-inflammatory, anti-angiogenetic, anti-arrhythmic and antioxidant activities, as well as anti-proliferative and proapoptotic effects in a wide range of human cancer cells. However, its effects on glioma cells are unknown. Here, we used different concentrations of honokiol in treating U251 and U-87 MG human glioma/glioblastoma cells in cell culture. Results showed that honokiol inhibited glioma cell viability and colony formation and promoted apoptosis. It also inhibited glioma cell migration/proliferation and invasion. In addition, honokiol promoted apoptosis and reduced Bcl-2 expression, accompanied by increase in Bax expression. Honokiol reduced expression of EGFR, CD133 and Nestin. Moreover, honokiol inhibited the activation of both AKT and ERK signaling pathways, increased active caspase-3 level and reduced phosphorylation of STAT3. U-87 MG xenografts in nude mice and in immunotolerant zebrafish yolk sac showed that honokiol inhibits tumor growth and metastasis. Altogether, results indicate that honokiol reduces tumorigenic potentials, suggesting hopes for honokiol to be useful in the clinical management of glioma/glioblastoma.
Highlights
Glioblastoma (GBM) is a highly lethal brain tumor that is resistant to most therapeutic means currently available
At concentrations of honokiol ranging from 0 to 60 μM, cell viability was dose-dependently reduced for U251 and U-87 MG cells compared with the vehicle control after treatment for 24 and 49 h (Figure 1A,B)
As was indicated by the number of cells having migrated to the underside of the transwell chamber, honokiol dose-dependently reduced the invasion ability of both cell lines when compared to vehicle control (Figure 2C,D)
Summary
Glioblastoma (GBM) is a highly lethal brain tumor that is resistant to most therapeutic means currently available. It accounts for 70% of human primary malignant brain tumors [1]. Cancer stem cells represent a subpopulation of tumor cells with enhanced clonogenic and tumorigenic potentials within a tumor [4]. A variety of tumors have been reported to contain a cell population with stem cell-like properties, including self-renewal and differentiation [5]. A number of tumor types, including gliomas, have shown the existence of a unique population of tumor/glioma initiating cells [4], which were initially isolated from human gliomas for isolating neural stem cells
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