Magnolol and honokiol exert a synergistic anti-tumor effect through autophagy and apoptosis in human glioblastomas

Cheng, Yu‐Chen; Hueng, Dueng‐Yuan; Huang, Huayin; Chen, Jang-Yi; Chen, Ying

doi:10.18632/oncotarget.8674

Cited by 47 publications

(32 citation statements)

References 45 publications

(46 reference statements)

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“…Magnolol and honokiol, extracted from Magnolia officinalis , inhibit GB progression by inducing cell cycle arrest and decreasing the expression of p-PI3K, p-AKT, suggesting proliferation inhibition. In addition, the treatment with magnolol and honokiol exerts a synergistic antitumor effect also by inducing autophagy and apoptosis in GB cells ( 76 ). Li et al reported that endothelial-monocyte-activating polypeptide II (EMAP 2), a tumor-derived pro-inflammatory cytokine, promoted autophagic vacuole formation and inhibited the PI3K/AKT/mTOR signaling pathway, thereby inducing autophagy and inhibiting the viability, migration, and angiogenesis of GB ( 77 ).…”

Section: The Role Of Autophagy In Glioblastoma Therapy With the Phospmentioning

confidence: 99%

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

Qin

Zhang

et al. 2020

Front. Oncol.

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Glioblastoma (GB) is the most malignant and aggressive form of brain tumor, characterized by frequent hyperactivation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. PI3K/AKT/mTOR inhibitors have a promising clinical efficacy theoretically. However, strong drug resistance is developed in GB against the PI3K/AKT/mTOR inhibitors due to the cytoprotective effect and the adaptive response of autophagy during the treatment of GB. Activation of autophagy by the PI3K/AKT/mTOR inhibitors not only enhances treatment sensitivity but also leads to cell survival when drug resistance develops in cancer cells. In this review, we analyze how to increase the antitumor effect of the PI3K/AKT/mTOR inhibitors in GB treatment, which is achieved by various mechanisms, among which targeting autophagy is an important mechanism. We review the dual role of autophagy in both GB therapy and resistance against inhibitors of the PI3K/AKT/mTOR signaling pathway, and further discuss the possibility of using combinations of autophagy and PI3K/AKT/mTOR inhibitors to improve the treatment efficacy for GB. Finally, we provide new perspectives for targeting autophagy in GB therapy.

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Section: The Role Of Autophagy In Glioblastoma Therapy With the Phospmentioning

confidence: 99%

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

Qin

Zhang

et al. 2020

Front. Oncol.

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“…The cytotoxicity of certain anti-tumor agents is induced by autophagy (29)(30)(31). To assess the association of autophagy with the pro-apoptotic effects of WZY-321, a number of autophagic markers were analyzed.…”

Section: Wzy-321 Enhances Autophagy In Shg-44 Glioma Cellsmentioning

confidence: 99%

WZY‑321, a novel evodiamine analog, inhibits glioma cell growth in an autophagy‑associated manner

Sun

Zhang²,

Song

et al. 2018

Oncol Lett

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Glioblastoma is one of the most aggressive types of brain tumor. The median survival rate of patients with glioblastoma (World Health Organization grade IV) is <15 months. Therefore, there is an urgent requirement for the development of novel and efficient therapeutic agents against glioma. In previous studies, WZY-321 (10-hydroxy-, a novel evodiamine (Evo) analog, was reported to exhibit enhanced pharmacological properties and improved cytotoxicity against a number of human cancer cell lines compared with Evo. In the current study, the anti-proliferative effect of WZY-321 on SHG-44 and SWO-38 glioma cells was further studied, and its mechanism of action investigated. The results indicated that WZY-321 inhibited the proliferation of SHG-44 cells in a dose-and time-dependent manner by enhancing cellular apoptosis and inducing cell cycle arrest at the G2-M phase. Treatment of glioma cells with WZY-321 concomitantly increased the expression levels of microtubule associated protein 1 light chain 3α and Beclin1, indicating enhanced autophagy. Overall, the results of the present study revealed the anti-proliferative potential of WZY-321 in glioma cells, thus providing a possible autophagy-based therapeutic strategy for the treatment of glioblastoma.

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“…It is now widely accepted that in response to various chemotherapeutic drugs, radiation, and targeted therapeutics, dying cells show large‐scale accumulation of autophagic vacuoles . Autophagy is also observed in the case of GBM in vitro and in vivo . TAM is widely accepted as a potent autophagy inducer .…”

Section: Introductionmentioning

confidence: 99%

“…22 Autophagy is also observed in the case of GBM in vitro and in vivo. 23,24 TAM is widely accepted as a potent autophagy inducer. 25 Graham et al 26 reported that TAM induces autophagic death in GBM cell lines and could provide new therapies for glioblastoma patients.…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor variant ER‐α36 promotes tamoxifen agonist activity in glioblastoma cells

Zhang

et al. 2019

Cancer Science

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Glioblastoma (GBM) is a highly infiltrative and malignant primary brain tumor. Despite aggressive therapy, patients with GBM have a dismal prognosis with median survival of approximately 1 year. Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), has been used to treat GBM for many years. ER‐α36 is a novel variant of estrogen receptor‐alpha66 (ER‐α66) and can mediate cell proliferation through estrogen or anti‐estrogen signaling in different cancer cells. Previously, we found that ER‐α36 was highly expressed in GBM and was involved in the tamoxifen sensitivity of glioblastoma cells. However, the molecular mechanism responsible has not been well established. Here, we found that ER‐α36 is highly expressed in glioblastoma specimens. We further found that ER‐α36 knockdown increased sensitivity of glioblastoma U87 cells to TAM and decreased autophagy in these cells. However, ER‐α36 overexpression decreased TAM sensitivity and induced autophagy. We also established TAM‐resistant glioblastoma U251 cells by a long‐term culture in TAM‐containing medium and found that TAM‐resistant cells showed a six‐fold increase of ER‐α36 mRNA expression and elevated basal autophagy. ER‐α36 knockdown in these TAM‐resistant cells restored TAM sensitivity. In addition, we recapitulated the physiologically relevant tumor microenvironment in an integrated microfluidic device, and U87 cells were treated with a gradient of TAM. We found that ER‐α36 expression is consistent with autophagy protein P62 in a three‐dimensional microenvironment. In summary, these results indicate that ER‐α36 contributes to tamoxifen resistance in glioblastoma cells presumably through regulation of autophagy.

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Magnolol and honokiol exert a synergistic anti-tumor effect through autophagy and apoptosis in human glioblastomas

Cited by 47 publications

References 45 publications

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

WZY‑321, a novel evodiamine analog, inhibits glioma cell growth in an autophagy‑associated manner

Estrogen receptor variant ER‐α36 promotes tamoxifen agonist activity in glioblastoma cells

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