The nitric oxide donor JS-K sensitizes U87 glioma cells to repetitive irradiation

Heckler, Max; Osterberg, Nadja; Guenzle, Jessica; Thiede-Stan, Nina Kristin; Reichardt, Wilfried; Weidensteiner, Claudia; Saavedra, Joseph E.; Weyerbrock, Astrid

doi:10.1177/1010428317703922

Cited by 10 publications

(5 citation statements)

References 35 publications

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“…However, this last phenomenon was not observed in M1 MΦ, suggesting another mechanism involved and more particularly the NO, as M1 MΦ are known to produce large amount of NO [ 33 ]. Indeed, NO can induce radiosensitization of cells under hypoxic conditions [ 34 – 36 ], including GB cells [ 37 , 38 ] by enhancing DNA DSBs [ 38 ], limiting DNA repair [ 39 ] and inducing mitotic catastrophe [ 37 ]. This could explain the mechanism involved in M1 radio-induced cell death as we have shown that M1 MΦ produced important quantity of NO which decreased in hypoxia, as already published [ 12 ], but still superior to the amount observed in M0 and M2 MΦ.…”

Section: Discussionmentioning

confidence: 99%

M2 macrophages are more resistant than M1 macrophages following radiation therapy in the context of glioblastoma

et al. 2017

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In some highly inflammatory tumors, such as glioblastoma (GB), macrophages (MΦ) represent the most abundant population of reactive cells. MΦ, initially denoted as M0 MΦ, can be polarized into two further phenotypes: the antitumor M1 MΦ, and the protumor M2 MΦ. The three phenotypes can reside simultaneously in the tumor mass and various external factors may influence MΦ polarization. Radiotherapy is a common modality of cancer treatment aiming to target tumor cells. However, the specific effects of X-ray radiation on the inflammatory cells are, so far, controversial and not fully understood. In the present investigation, we have first analyzed, in vivo, the effect of X-ray radiation on MΦ present in GB tumors. We have observed a decrease in MΦ number paralleled by an increase in the proportion of M2 MΦ. To understand this phenomenon, we then evaluated, in vitro, the effects of X-rays on the MΦ phenotypes and survival. We have found that X-ray radiation failed to modify the phenotype of the different MΦ. However, M1 MΦ were more sensitive to ionizing radiation than M2 MΦ, both in normoxia and in hypoxia, which could explain the in vivo observations. To conclude, M2 MΦ are more radioresistant than M0 and M1 MΦ and the present study allows us to propose that X-ray radiotherapy could contribute, along with other phenomena, to the increased density in the protumor M2 MΦ in GB.

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Section: Discussionmentioning

confidence: 99%

M2 macrophages are more resistant than M1 macrophages following radiation therapy in the context of glioblastoma

et al. 2017

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“…Briefly, reactive oxygen species and their inducers have been found to sensitize tumor cells to apoptosis (Table 2). Small molecules, such as nitric oxide donors, can also sensitize resistant tumor cells to immunotherapy, chemotherapy [56], and radiation therapy [57]. Thus, nitric oxide donors and other agents that can increase the localized production of reactive oxygen species may be effective for use in combination therapies and overcoming drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Hays

Bonavida

2019

Antioxidants

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In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression.

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“…Although it was identified that the DNA profile of U87MG cells was different from that of the original cells in 2016, it is likely to be a bona fide human glioblastoma cell line of unknown origin (23). These cells are thought to exhibit the characteristics of human glioblastoma (24)(25)(26)(27), including proliferation, invasion and migration. The U87 cell line remains one of the most representative glioma cell lines.…”

Section: Discussionmentioning

confidence: 99%

MAP30 promotes apoptosis of U251 and U87 cells by suppressing the LGR5 and Wnt/β-catenin signaling pathway, and enhancing Smac expression

et al. 2018

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Abstract. Significant antitumor activity of Momordica anti-human immunodeficiency virus protein of 30 kDa (MAP30) purified from Momordica charantia has been the subject of previous research. However, the effective mechanism of MAP30 on malignant glioma cells has not yet been clarified. The aim of the present study was to investigate the effects and mechanism of MAP30 on U87 and U251 cell lines. A Cell Counting Kit-8 assay, wound healing assay and Transwell assay were used to detect the effects on U87 and U251 cells treated with different concentrations of MAP30 (0.5, 1, 2, 4, 8 and 16 µM) over different periods of time. Proliferation, migration and invasion of each cell line were markedly inhibited by MAP30 in a dose-and time-dependent manner. Flow cytometry and fluorescence staining demonstrated that apoptosis increased and the cell cycle was arrested in S-phase in the two investigated cell lines following MAP30 treatment. Western blot analysis demonstrated that leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5) expression and key proteins in the Wnt/β-catenin signaling pathway were apparently decreased, whereas second mitochondria-derived activator of caspase (Smac) protein expression significantly increased with MAP30 treatment in the same manner. These results suggest that MAP30 markedly induces apoptosis in U87 and U251 cell lines by suppressing LGR5 and the Wnt/β-catenin signaling pathway, and enhancing Smac expression in a dose-and time-dependent manner.

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The nitric oxide donor JS-K sensitizes U87 glioma cells to repetitive irradiation

Cited by 10 publications

References 35 publications

M2 macrophages are more resistant than M1 macrophages following radiation therapy in the context of glioblastoma

M2 macrophages are more resistant than M1 macrophages following radiation therapy in the context of glioblastoma

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

MAP30 promotes apoptosis of U251 and U87 cells by suppressing the LGR5 and Wnt/β-catenin signaling pathway, and enhancing Smac expression

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