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Newcastle disease virus enhances the growth-inhibiting and proapoptotic effects of temozolomide on glioblastoma cells in vitro and in vivo.

ABSTRACT: Glioblastoma (GBM) is the most serious and most common brain tumor in humans. Despite recent advances in the diagnosis of GBM and the development of new treatments, the prognosis of patients has not improved. Multidrug resistance, particularly resistance to temozolomide (TMZ), is a challenge in combating glioma, and more effective therapies are needed. Complementary treatment with the LaSota strain of the naturally oncolytic Newcastle disease virus (NDV-LaSota) is an innovation. In our experiments, the combination therapy of NDV-LaSota and temozolomide (TMZ) was more effective than either treatment alone in inducing apoptosis in glioma cells. NDV can function as a tumor cell selective approach to inhibit AKT and activate AMPK. Consequently, mTOR, 4EBP1 and S6K were also suppressed. The combination therapy of NDV and TMZ also significantly extended survival in a rat xenograft tumor model. In conclusion, NDV suppress AKT signaling and enhances antitumor effects of TMZ. Our study provides one of the theoretical basis for the use of a combined therapy of TMZ and NDV, which could benefit GBM patients.

SUBMITTER: Bai Y

PROVIDER: S-EPMC6068118 | biostudies-other | 2018 Jul

REPOSITORIES: biostudies-other

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Newcastle disease virus enhances the growth-inhibiting and proapoptotic effects of temozolomide on glioblastoma cells in vitro and in vivo.

Bai Yang Y Chen Yong Y Hong Xinyu X Liu Xinrui X Su Xing X Li Shanji S Dong Xuechao X Zhao Gang G Li Yunqian Y

Scientific reports 20180731 1

Glioblastoma (GBM) is the most serious and most common brain tumor in humans. Despite recent advances in the diagnosis of GBM and the development of new treatments, the prognosis of patients has not improved. Multidrug resistance, particularly resistance to temozolomide (TMZ), is a challenge in combating glioma, and more effective therapies are needed. Complementary treatment with the LaSota strain of the naturally oncolytic Newcastle disease virus (NDV-LaSota) is an innovation. In our experimen ...[more]

PMID: 30065314

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Project description:BackgroundUltrasound-triggered microbubble destruction (UTMD) is a widely used noninvasive technology in both military and civilian medicine, which could enhance radiosensitivity of various tumors. However, little information is available regarding the effects of UTMD on radiotherapy for glioblastoma or the underlying mechanism. This study aimed to delineate the effect of UTMD on the radiosensitivity of glioblastoma and the potential involvement of autophagy.MethodsGL261, U251 cells and orthotopic glioblastoma-bearing mice were treated with ionizing radiation (IR) or IR plus UTMD. Autophagy was observed by confocal microscopy and transmission electron microscopy. Western blotting and immunofluorescence analysis were used to detect progesterone receptor membrane component 1 (PGRMC1), light chain 3 beta 2 (LC3B2) and sequestosome 1 (SQSTM1/p62) levels. Lentiviral vectors or siRNAs transfection, and fluorescent probes staining were used to explore the underlying mechanism.ResultsUTMD enhanced the radiosensitivity of glioblastoma in vitro and in vivo (P < 0.01). UTMD inhibited autophagic flux by disrupting autophagosome-lysosome fusion without impairing lysosomal function or autophagosome synthesis in IR-treated glioblastoma cells. Suppression of autophagy by 3-methyladenine, bafilomycin A1 or ATG5 siRNA had no significant effect on UTMD-induced radiosensitization in glioblastoma cells (P < 0.05). Similar results were found when autophagy was induced by rapamycin or ATG5 overexpression (P > 0.05). Furthermore, UTMD inhibited PGRMC1 expression and binding with LC3B2 in IR-exposed glioblastoma cells (P < 0.01). PGRMC1 inhibitor AG-205 or PGRMC1 siRNA pretreatment enhanced UTMD-induced LC3B2 and p62 accumulation in IR-exposed glioblastoma cells, thereby promoting UTMD-mediated radiosensitization (P < 0.05). Moreover, PGRMC1 overexpression abolished UTMD-caused blockade of autophagic degradation, subsequently inhibiting UTMD-induced radiosensitization of glioblastoma cells. Finally, compared with IR plus UTMD group, PGRMC1 overexpression significantly increased tumor size [(3.8 ± 1.1) mm2 vs. (8.0 ± 1.9) mm2, P < 0.05] and decreased survival time [(67.2 ± 2.6) d vs. (40.0 ± 1.2) d, P = 0.0026] in glioblastoma-bearing mice.ConclusionUTMD enhanced the radiosensitivity of glioblastoma partially by disrupting PGRMC1-mediated autophagy.

Dataset Information

Newcastle disease virus enhances the growth-inhibiting and proapoptotic effects of temozolomide on glioblastoma cells in vitro and in vivo.

Publications

Newcastle disease virus enhances the growth-inhibiting and proapoptotic effects of temozolomide on glioblastoma cells in vitro and in vivo.

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