Multiple cytotoxic effects of gamabufotalin against human glioblastoma cell line U-87

Yuan, Bo; Shimada, Ryota; Xu, Kang; Han, Lijun; Si, Nan; Zhao, Haiyu; Bian, Baolin; Hayashi, Hideki; Okazaki, Mari; Takagi, Norio

doi:10.1016/j.cbi.2019.108849

Cited by 23 publications

(37 citation statements)

References 55 publications

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“…Following treatment for 48 h with various indicated concentrations of As III and gamabufotalin, alone or in combination, cell viability was measured by the XTT assay as described previously ( 36 , 38 ). Relative cell viability was expressed as the ratio of the absorbance at 450 nm of each treatment group against those of the corresponding untreated control group.…”

Section: Methodsmentioning

confidence: 99%

“…Following treatment for 48 h with indicated concentrations of As III and gamabufotalin, alone or in combination, LDH leakage from U-87 cells was measured using a LDH cytotoxicity detection kit (Wako Pure Chemical Industry) according to the method previously described with slight modifications ( 19 , 36 ). Briefly, culture medium served as the negative control (NC).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, p38 kinase, a member of the mitogen-activated protein kinases (MAPKs) family, has been considered to be positively related to diverse cellular processes including cell cycle arrest and cell death signaling ( 31 – 33 ). Inversely, a novel prosurvival role of p38 MAPK has been demonstrated in human cancer cells such as glioblastoma cells ( 19 , 34 – 36 ). Despite this, the molecular events underlying the potential cytotoxic effects caused by As III and gamabufotalin, alone or in combination, against glioblastoma cells remain to be seen.…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxic Effects of Arsenite in Combination With Gamabufotalin Against Human Glioblastoma Cell Lines

Yuan

Shimada

et al. 2021

Front. Oncol.

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Glioblastoma is a fatal primary malignant brain tumor, and the 5-year survival rate of treated glioblastoma patients still remains <5%. Considering the sustained development of metastasis, tumor recurrence, and drug resistance, there is an urgent need for the novel therapeutic approaches to combat glioblastoma. Trivalent arsenic derivative (arsenite, AsIII) with remarkable clinical efficacy in leukemia has been shown to exert cytocidal effect against glioblastoma cells. Gamabufotalin, an active bufadienolide compound, also shows selective cytocidal effect against glioblastoma cells, and has been suggested to serve as a promising adjuvant therapeutic agent to potentiate therapeutic effect of conventional anticancer drugs. In order to gain novel insight into therapeutic approaches against glioblastoma, the cytotoxicity of AsIII and gamabufotalin was explored in the human glioblastoma cell lines U-87 and U-251. In comparison with U-251 cells, U-87 cells were highly susceptible to the two drugs, alone or in combination. More importantly, clinically achieved concentrations of AsIII combined with gamabufotalin exhibited synergistic cytotoxicity against U-87 cells, whereas showed much less cytotoxicity to human normal peripheral blood mononuclear cells. G2/M cell cycle arrest was induced by each single drug, and further augmented by their combination in U-87 cells. Downregulation of the expression levels of cdc25C, Cyclin B1, cdc2, and survivin was observed in U-87 cells treated with the combined regimen and occurred in parallel with G2/M arrest. Concomitantly, lactate dehydrogenase leakage was also observed. Intriguingly, SB203580, a specific inhibitor of p38 MAPK, intensified the cytotoxicity of the combined regimen in U-87 cells, whereas wortmannin, a potent autophagy inhibitor, significantly rescued the cells. Collectively, G2/M arrest, necrosis and autophagy appeared to cooperatively contribute to the synergistic cytotoxicity of AsIII and gamabufotalin. Given that p38 MAPK serves an essential role in promoting glioblastoma cell survival, developing a possible strategy composed of AsIII, gamabufotalin, and a p38 MAPK inhibitor may provide novel insight into approaches designed to combat glioblastoma.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cytotoxic Effects of Arsenite in Combination With Gamabufotalin Against Human Glioblastoma Cell Lines

Yuan

Shimada

et al. 2021

Front. Oncol.

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“…The Ras/Raf/ERK signaling pathway is one of the most frequent pathways that activate macroautophagy in tumors [54,55]. Other important modulators of macroauthophagy in GB are Sirt1 that induces autophagic cell death and mitophagy [56], insulin, p53 [57], p38 mitogen-activated protein kinase (p38-MAPK) [58], 5 AMPK [59], phosphatase and tensin homolog deleted from chromosome 10 (PTEN) [60], and reactive oxygen species (ROS)-associated pathways [61]. Furthermore, intracellular calcium signaling seems also an important regulatory pathway in GB [62,63].…”

Section: Regulationmentioning

confidence: 99%

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

Molina

García‐Bernal

Valdor

2019

Cancers

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Glioblastoma (GB) has been shown to up-regulate autophagy with anti- or pro-oncogenic effects. Recently, our group has shown how GB cells aberrantly up-regulate chaperone-mediated autophagy (CMA) in pericytes of peritumoral areas to modulate their immune function through cell-cell interaction and in the tumor’s own benefit. Thus, to understand GB progression, the effect that GB cells could have on autophagy of immune cells that surround the tumor needs to be deeply explored. In this review, we summarize all the latest evidence of several molecular and cellular immunosuppressive mechanisms in the perivascular tumor microenvironment. This immunosuppression has been reported to facilitate GB progression and may be differently modulated by several types of autophagy as a critical point to be considered for therapeutic interventions.

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“…The cell viability was measured by XTT dye-reduction assay as described previously (Yoshino et al, 2018;Yuan et al, 2019). Relative cell viability was expressed as the ratio of the absorbance of each treatment group against that of the corresponding untreated control group.…”

Section: Cell Viability Assaymentioning

confidence: 99%

JNK and Autophagy Independently Contributed to Cytotoxicity of Arsenite combined With Tetrandrine via Modulating Cell Cycle Progression in Human Breast Cancer Cells

Yuan

et al. 2020

Front. Pharmacol.

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Novel therapeutic strategies for breast cancer are urgently needed due to the sustained development of drug resistance and tumor recurrence. Trivalent arsenic derivative (arsenite, As III) has been reported to induce cytotoxicity in breast cancer cells. We recently demonstrated that As III plus tetrandrine (Tetra), a Chinese plant-derived alkaloid, exerted potent antitumor activity against human breast cancer cells, however, the underlying mechanisms for their action have not been well defined. In order to provide fundamental insights for understanding the action of As III plus Tetra, the effects of the combined regimen on two breast cancer cell lines T47D and MDA-MB-231 were evaluated. Compared to T47D cells, MDA-MB-231 cells were much more susceptible to the synergistic cytotoxic effects of As III and Tetra. Besides the induction of apoptotic/ necrotic cell death, S-phase arrest and autophagic cell death were also observed in MDA-MB-231 cells. Exposure of MDA-MB-231 cells to As III and Tetra caused the activation of MAPKs. Cytotoxicity of the combined regimen in MDA-MB-231 cell was significantly abrogated by SP600125, a potent c-Jun N-terminal kinase (JNK) inhibitor. However, similar abrogation was not caused by p38 and ERK inhibitors. The addition of either autophagy inhibitors (3-methyladenine or wortmannin) or SP600125 corrected the combined regimen-triggered S-phase arrest, whereas had little effect on the apoptosis/ necrosis induction in the cells. Surprisingly, SP600125NC, a negative control for SP600125, significantly strengthened S-phase arrest and the cytotoxicity induced by

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Multiple cytotoxic effects of gamabufotalin against human glioblastoma cell line U-87

Cited by 23 publications

References 55 publications

Cytotoxic Effects of Arsenite in Combination With Gamabufotalin Against Human Glioblastoma Cell Lines

Cytotoxic Effects of Arsenite in Combination With Gamabufotalin Against Human Glioblastoma Cell Lines

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

JNK and Autophagy Independently Contributed to Cytotoxicity of Arsenite combined With Tetrandrine via Modulating Cell Cycle Progression in Human Breast Cancer Cells

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