Targeting autophagy to sensitive glioma to temozolomide treatment

Yan, Yuanliang; Xu, Zhijie; Dai, Shuang; Qian, Long; Sun, Lun‐Quan

doi:10.1186/s13046-016-0303-5

Cited by 257 publications

(212 citation statements)

References 116 publications

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“…This finding is of clinical relevance and in addition with reports of SAS as a sensitizer for radiotherapy [31] could implement this xCT inhibitor as a new modality in glioblastoma therapy. But in comparison to TMZ, SAS–mediated effects on glioma cell survival did not appear to rely on significant alterations in the mechanism of autophagy [32]. Instead, SAS can induce ferroptosis in glioma cells.…”

Section: Discussionmentioning

confidence: 99%

Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema

et al. 2016

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The glutamate transporter xCT (SCL7a11, system Xc-, SXC) is an emerging key player in glutamate/cysteine/glutathione homeostasis in the brain and in cancer. xCT expression correlates with the grade of malignancy. Here, we report on the use of the U.S. Food and Drug Administration and EMA-approved xCT inhibitor, sulfasalazine (SAS) in gliomas. SAS does not affect cell viability in gliomas at concentrations below 200 μM. At higher concentrations SAS becomes gliomatoxic. Mechanistically SAS inhibits xCT and induces ferroptotic cell death in glioma cells. There is no evidence for impact on autophagic flux following SAS application. However, SAS can potentiate the efficacy of the standard chemotherapeutic and autophagy-inducing agent temozolomide (Temcat, Temodal or Temodar®). We also investigated SAS in non-transformed cellular constituents of the brain. Neurons and brain tissue are almost non-responding to SAS whereas isolated astrocytes are less sensitive towards SAS toxicity compared to gliomas. In vivo SAS treatment does not affect experimental tumor growth and treated animals revealed comparable tumor volume as untreated controls. However, SAS treatment resulted in reduced glioma-derived edema and, hence, total tumor volume burden as revealed by T2-weighted magnetic resonance imaging. Altogether, we show that SAS can be utilized for targeting the glutamate antiporter xCT activity as a tumor microenvironment-normalizing drug, while crucial cytotoxic effects in brain tumors are minor.

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Section: Discussionmentioning

confidence: 99%

Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema

et al. 2016

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“…This kinase has a specific role in the DNA double-strand breaks repair, that is exercised in the nucleus, and a cytoplasmic function that is related to autophagy [33], a process that may be implied in therapy resistance [34]. …”

Section: Discussionmentioning

confidence: 99%

Can recurrences be predicted in craniopharyngiomas? β-catenin coexisting with stem cells markers and p-ATM in a clinicopathologic study of 45cases

Guadagno

Solari

Borrelli

et al. 2017

J Exp Clin Cancer Res

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BackgroundRecurrence is a common feature of craniopharyngiomas, benign tumors that origin from squamous epithelial remnants of Rathke’s pouch- arising at any segment of its whole course. There are two histotypes, showing different morphology and clinical behavior: adamantinomatous(adaCP) and papillary (papCP). An univocal strategy of management has not yet been defined, being considered the combination of surgery and radiotherapy the most effective, especially in case of incomplete resection. Therefore, the identification of factors influencing the biological and clinical behaviour is of paramount importance.β-catenin is a cell-cell adhesion protein, whose nuclear localization has been linked to the pathogenesis of adaCP: its nuclear accumulation is associated to the presence of a tumor stem cell subpopulation. The latter is made of cells capable of self-renewal, hence believed to be responsible of recurrence, metastases and resistance to therapy in all tumors.ATM is a kinase activated by autophosphorylation (p-ATM) upon DNA double-strand breaks. It is involved not only in DNA repair, but also in tumor migration and invasiveness. Its expression may have prognostic implications in many neoplastic diseases.MethodsIn this study, we measured the immunohistochemical expression of β-catenin, stem cell markers (CD133, CD166), Ki67 and pATMin 45 craniopharyngiomas and correlated it with clinicopathologic features.ResultsStatistical analysis revealed strong correlation of β-catenin with recurrence (p = 0.0039), Ki67 (p = 0.0011, r = 0.4903) and CD166 (p = 0.0002, r = 0.6218). A slight tendency to a higher expression of β-catenin was recorded for adaCP rather than papCP (p = 0.0895).Fisher’s exact test showed that CD166 was significantlyrelated with recurrence (p = 0.0040). Furthermore, cytoplasmic pATM was more expressed in adaCPs (p = 0.0470), compared to papCPs that displayed a more evident nuclear signal (p = 0.0313) instead.ConclusionsBacking upon these data, we could weigh in on the need of identifying β-catenin and CD166 as prognostic markersthat could be useful in predicting thebiologicalbehavior, as recurrence risk incraniopharyngiomas. The final goal is to drew up a prognostic algorithm to be of aid in the planning of an appropriate treatment strategy. Furthermore, our findings demonstrate that pATM could be used as additional distinction-marker between the two histotypes.

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“…Apoptosis is an important mechanism for the regulation of sensitivity to radiation [9, 27]. We found that overexpression of miR-19b-3p or knockout of TNFAIP3 decreased apoptosis rates of NPC cell lines after irradiation.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-19b-3p regulates nasopharyngeal carcinoma radiosensitivity by targeting TNFAIP3/NF-κB axis

Huang

et al. 2016

J Exp Clin Cancer Res

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BackgroundNasopharyngeal carcinoma (NPC) is among the most common squamous cell carcinoma in South China and Southeast Asia. Radiotherapy is the primary treatment for NPC. However, radioresistance acts as a significant factor that limits the efficacy of radiotherapy for NPC patients. Growing evidence supports that microRNAs (miRNAs) play an important role in radiation response.MethodsReal-time quantitative PCR was used to analyze the expression of miR-19b-3p in NPC cell lines and NP69. miR-19b-3p expression profiles in NPC tissues were obtained from the Gene Expression Omnibus database. The effect of miR-19b-3p on radiosensitivity was evaluated by cell viability assays, colony formation assays and in vivo experiment. Apoptosis and cell cycle were examined by flow cytometry. Luciferase reporter assay was used to assess the target genes of miR-19b-3p. Expression of target proteins and downstream molecules were analyzed by Western blot.ResultsmiR-19b-3p was upregulated in NPC and served as an independent predictor for reduced patient survival. Radioresponse assays showed that miR-19b-3p overexpression resulted in decreased sensitivity to irradiation, whereas miR-19b-3p downregulation resulted in increased sensitivity to irradiation in vitro. Moreover, miR-19b-3p decreased the sensitivity of NPC cells to irradiation in vivo. Luciferase reporter assay confirmed that TNFAIP3 was a direct target gene of miR-19b-3p. Knockdown of TNFAIP3 reduced sensitivity to irradiation, whereas upregulation of TNFAIP3 expression reversed the inhibitory effects of miR-19b-3p on NPC cell radiosensitivity. Mechanistically, we found that miR-19b-3p increased NPC cell radioresistance by activating the TNFAIP3/ NF-κB axis.ConclusionsmiR-19b-3p contributes to the radioresistance of NPC by activating the TNFAIP3/ NF-κB axis. miR-19b-3p is a determinant of NPC radioresponse and may serve as a potential therapeutic target in NPC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0465-1) contains supplementary material, which is available to authorized users.

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Targeting autophagy to sensitive glioma to temozolomide treatment

Cited by 257 publications

References 116 publications

Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema

Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema

Can recurrences be predicted in craniopharyngiomas? β-catenin coexisting with stem cells markers and p-ATM in a clinicopathologic study of 45cases

MicroRNA-19b-3p regulates nasopharyngeal carcinoma radiosensitivity by targeting TNFAIP3/NF-κB axis

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