The DNA demethylating agent 5‐aza‐2′‐deoxycytidine activates NY‐ESO‐1 antigenicity in orthotopic human glioma

Natsume, Atsushi; Wakabayashi, Toshihiko; Tsujimura, Kunio; Shimato, Shinji; Ito, Motokazu; Kuzushima, Kiyotaka; Kondo, Yutaka; Sekido, Yoshitaka; Kawatsura, Hitomi; Narita, Yuji; Yoshida, Jun

doi:10.1002/ijc.23407

Cited by 88 publications

(71 citation statements)

References 42 publications

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“…One way to bypass this lack of identified antigens for MPM is to force tumour cells to express tumour-associated antigens (TAAs). With the aim of favouring TAA expression, it has been shown that hypomethylating drugs and/or HDAC inhibitors, in addition to restoring a normal epigenetic status in cancer cells, can also induce tumour antigen expression [17][18][19][20][21].…”

Section: Alignant Pleural Mesothelioma (Mpm)mentioning

confidence: 99%

A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma

et al. 2011

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Malignant pleural mesothelioma (MPM) is an aggressive tumour with a limited response to conventional therapy. The aim of this study was to evaluate the anticancer effect of a DNA methyltransferase inhibitor, 5-aza-29-deoxycytidine (5-azaCdR), and two histone deacetylase inhibitors, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA).Human mesothelioma cells were treated with each epigenetic drug, either alone or in combinations. The cytotoxic effects on treated cells and the expression of specific tumour antigens were evaluated. The recognition of treated cells by a specific CD8+ T-cell clone was also measured. Additionally, the effect of combined treatments was tested in a murine model of mesothelioma.We showed that VPA and SAHA synergised with 5-azaCdR to kill MPM cells and induce tumour antigen expression in the remaining living tumour cells. As a consequence, tumour cells expressing these antigens were recognised and lysed by specific CD8+ cytotoxic T-cells. In vivo, treatment with 5-azaCdR/VPA inhibited tumour growth, and promoted lymphocyte infiltration and an immune response against tumour cells.Appropriate epigenetic drug combinations, in addition to inducing mesothelioma cell death, also affect the immunogenic status of these cells. This property could be exploited in clinical investigations to develop MPM treatments combining chemotherapeutic and immunotherapeutic approaches.

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Section: Alignant Pleural Mesothelioma (Mpm)mentioning

confidence: 99%

A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma

et al. 2011

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“…Female 7-week-old mice nonobese diabetic/severe combined immunodeficiency disease (NOD/SCID) were used as described previously. 32 All mice were purchased from Charles River Lavoratories, Osaka, Japan. Mice were anaesthetized with an intraperitoneal injection of pentobarbital (60-70 mg/ kg body weight).…”

Section: Cell Migration and Invasion Assaymentioning

confidence: 99%

Sphingosine‐1‐phosphate receptor type 1 regulates glioma cell proliferation and correlates with patient survival

Yoshida¹,

Nakada²,

Sugimoto³

et al. 2010

Intl Journal of Cancer

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Sphingosine-1-phosphate (S1P) is a bioactive lipid that signals through a family of G protein-coupled receptors consisting of 5 members termed S1P 1-5 , and it regulates cellular proliferation, migration and survival. We investigated the expression and role of S1P receptors in glioma. Human glioma expressed S1P 1 , S1P 2 , S1P 3 , and S1P 5 by quantitative real-time PCR analysis. Expression of the S1P 1 was significantly lower in glioblastoma than in the normal brain (p < 0.01) and diffuse astrocytoma (p < 0.05). Immunoblotting showed that normal brain expressed more S1P 1 protein than did glioblastoma. Immunohistochemistry showed that S1P 1 was localized predominantly in the astrocytes in the normal brain, but no staining was observed in glioblastoma. Downregulation of S1P 1 expression correlated with poor survival of patients with glioblastoma (p < 0.05). S1P 1 small interfering RNA promoted cell proliferation in high-expressor glioma cell lines (T98G, G112). Cell proliferation was promoted by the pertussis toxin, which deactivates G i/o type of G proteins; the S1P 1 is exclusively coupled to these proteins. Forced expression of the S1P 1 in low-expressor cell lines (U87, U251) resulted in decreased cell growth and led to suppressed tumor growth in transplanted gliomas in vivo. Furthermore, we found a significant association between the S1P 1 expression and early growth response-1, a transcriptional factor that exhibits tumor suppression in glioblastoma cells (p < 0.05). These data indicate that the downregulation of S1P 1 expression enhances the malignancy of glioblastoma by increasing cell proliferation and correlates with the shorter survival of patients with glioblastoma.

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“…We stereotactically injected 0316-GICs (1 × 10 5 cells) resuspended in 5 μL of PBS into 5-to 6-wk-old nonobese diabetic/severe combined immunodeficient female mice (SLC, Shizuoka, Japan) as described previously (40). IFN-β (2 × 10 5 IU/animal) was given i.p.…”

Section: Intracranial Glioma Xenograft and Ifn-β Treatmentmentioning

confidence: 99%

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

Ohno

Natsume

Kondo

et al. 2009

Molecular Cancer Research

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Type I IFNs are involved in double-stranded RNA responses. Here, we investigated the possibility that IFN-β may induce or downregulate cellular microRNAs (miRNA) in human neoplasms and thereby use the RNA interference system to show antitumor effects. Because of its known connection to glioma biology, we focused on miR-21 among seven miRNAs influenced by IFN-β. We analyzed the effect of IFN-β treatment on miR-21 expression in glioma cells and intracranial glioma xenografts. IFN-β treatment reduced miR-21 expression in glioma cells markedly, and IFN-β administration suppressed the growth of glioma-initiating cell-derived intracranial tumors. The levels of primary miR-21 gene transcripts, precursor miR-21, and mature miR-21 decreased 6 hours after the addition of IFN-β, indicating that the reduction in miR-21 levels was due to transcriptional suppression. We did reporter assays to elucidate the IFN-β-mediated suppression of miR-21; the addition of signal transducers and activators of transcription 3 (STAT3)-expressing vectors induced the IFN-β-mediated suppression of miR-21, whereas STAT3-inhibiting agents inhibited the miR-21 suppression. Thus, the results of our study show that the downregulation of miR-21 contributes to the antitumor effects of IFN-β and that miR-21 expression is negatively regulated by STAT3 activation. These results highlight the importance of understanding the transcriptional regulation of the miRNAs involved in

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The DNA demethylating agent 5‐aza‐2′‐deoxycytidine activates NY‐ESO‐1 antigenicity in orthotopic human glioma

Cited by 88 publications

References 42 publications

A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma

A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma

Sphingosine‐1‐phosphate receptor type 1 regulates glioma cell proliferation and correlates with patient survival

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

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