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Radiation therapy is among the most essential treatment methods for glioblastoma multiforme (GBM). Radio-resistance and cancer stem cell properties can cause therapeutic resistance, cancer heterogeneity, and poor prognoses in association with GBM. Furthermore, the GBM subtype transition from proneural to the most malignant mesenchymal subtype after radiation therapy also accounts for high resistance to conventional treatments. Here, we demonstrate that the inhibition of macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (DDT) by 4-iodo-6-phenylpyrimidine (4-IPP), a dual inhibitor targeting MIF and DDT, downregulates stemness phenotype, intracellular signaling cascades, mesenchymal trans-differentiation, and induces apoptosis in proneural glioma stem cells (GSCs). In an analysis of The Cancer Genome Atlas, high MIF and DDT expression were associated with poor prognosis. GSC growth was effectively inhibited by 4-IPP in a time- and dose-dependent manner, and 4-IPP combined with radiation therapy led to significantly reduced proliferation compared with radiation therapy alone. The expression of stemness factors, such as Olig2 and SOX2, and the expression of pAKT, indicating PI3K signaling pathway activation, were decreased in association with both 4-IPP monotherapy and combination treatment. The expression of mesenchymal markers, TGM2 and NF-κB, and expression of pERK (indicating MAPK signaling pathway activation) increased in association with radiation therapy alone but not with 4-IPP monotherapy and combination therapy. In addition, the combination of 4-IPP and radiation therapy significantly induced apoptosis compared to the monotherapy of 4-IPP or radiation. In vivo results demonstrated a significant tumor-suppressing effect of 4-IPP when combined with radiation therapy. Collectively, our results showed that the targeted inhibition of MIF and DDT has the potential to strengthen current clinical strategies by enhancing the anticancer effects of radiation therapy. [ABSTRACT FROM AUTHOR]

Introduction: Recently, electric cigarettes with liquid (e-liquid) were introduced as an alternative to tobacco smoking. They were promoted as possible cessation aids and were considered to be potentially less harmful than traditional tobacco-based cigarettes. However, there is little information on the toxicants present in e-liquids and their possible carcinogenic effects. Methods: Western blot analysis was performed to identify the protein levels of cancer progression related signal transducers. Patient-derived brain tumor cells (CSC2) were injected into mouse brains and tumor growth was then observed by performing magnetic resonance imaging (MRI) and hematoxylin and eosin (H&E) staining of the whole brain. Immunohistochemistry (IHC) staining and Immunofluorescence staining were performed to study the expression of pEGFR and pERK. Results: Western blotting revealed that e-liquids increased pEGFR and pERK expression in a dose dependent manner. Animal experiments revealed that the e-liquid treated group had accelerated tumor growth and poor prognosis compared to the vehicle group. Histological staining showed activation of pEGFR and pERK in the e-liquid treated group. Conclusion: Our study revealed that e-liquid activates pEGFR and pERK, leading to accelerated brain tumor growth and poor prognosis. [ABSTRACT FROM AUTHOR]