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Anti-tumor effects of suberoylanilide hydroxamic acid on Epstein-Barr virus-associated T cell and natural killer cell lymphoma.

Siddiquey MN, Nakagawa H, Iwata S, Kanazawa T, Suzuki M, Imadome K, Fujiwara S, Goshima F, Murata T, Kimura H - Cancer Sci. (2014)

Bottom Line: Recent studies have reported that histone deacetylase (HDAC) inhibitors exert anticancer effects against various tumor cells.In addition, SAHA increased the expression of EBV-lytic genes and decreased the expression of EBV-latent genes.SAHA displayed a marked suppressive effect against EBV-associated T and NK cell lymphomas through either induction of apoptosis or cell cycle arrest, and may represent an alternative treatment option.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

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Related in: MedlinePlus

Suberoylanilide hydroxamic acid (SAHA) inhibits tumor growth and metastasis of Epstein–Barr virus (EBV)-positive natural killer (NK) cell lymphoma. (a) SNK6 cells (1 × 106 per mouse) were inoculated subcutaneously into NOG mice. Mice were treated with 100 mg/kg SAHA or DMSO (control) daily from days 4 to 28. Tumor sizes were measured twice per week. (b) At 30 days after inoculation, mice were killed, and Epstein–Barr virus-encoded small RNA-positive cells were detected by in situ hybridization in tumor tissues of SAHA-treated or control mice (scale bars: 200 μm). (c) At 30 days after inoculation, peripheral blood was collected, and plasma was separated. EBV-DNA was quantified by real-time PCR. (d) At 30 days, EBV-related gene expression in tumor tissues was quantified. β2-Microglobulin was used for relative quantification and assigned an arbitrary value of 1 (100). (e) EBER-positive cells, which meant EBV-positive lymphoma cells, were detected by in situ hybridization in organ tissues of SAHA-treated or control mice (scale bars: 200 μm). *P < 0.05, **P < 0.01, ***P < 0.002 by Mann–Whitney U-test.
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fig07: Suberoylanilide hydroxamic acid (SAHA) inhibits tumor growth and metastasis of Epstein–Barr virus (EBV)-positive natural killer (NK) cell lymphoma. (a) SNK6 cells (1 × 106 per mouse) were inoculated subcutaneously into NOG mice. Mice were treated with 100 mg/kg SAHA or DMSO (control) daily from days 4 to 28. Tumor sizes were measured twice per week. (b) At 30 days after inoculation, mice were killed, and Epstein–Barr virus-encoded small RNA-positive cells were detected by in situ hybridization in tumor tissues of SAHA-treated or control mice (scale bars: 200 μm). (c) At 30 days after inoculation, peripheral blood was collected, and plasma was separated. EBV-DNA was quantified by real-time PCR. (d) At 30 days, EBV-related gene expression in tumor tissues was quantified. β2-Microglobulin was used for relative quantification and assigned an arbitrary value of 1 (100). (e) EBER-positive cells, which meant EBV-positive lymphoma cells, were detected by in situ hybridization in organ tissues of SAHA-treated or control mice (scale bars: 200 μm). *P < 0.05, **P < 0.01, ***P < 0.002 by Mann–Whitney U-test.

Mentions: We subcutaneously inoculated 1 × 106 SNK6 cells into NOG mice. All of the mice developed tumors at the site of inoculation. Four days after the inoculation, mice were treated with SAHA daily up to day 28. The treated mice normally tolerated SAHA without showing any obvious toxicity. During this period, no significant difference in the body weights of SAHA-treated and control mice was noted (data not shown). Until the end of the experiment, the size of tumors in SAHA-treated mice increased gradually, but the tumor volume was significantly less than the control group (Fig.7a). EBER ISH showed the extent of the tumor in each mouse (Fig.7b). In the SAHA-treated mouse, the tumor was regressed with degeneration. Additionally, SAHA-treated mice showed a significantly lower plasma EBV-DNA level (Fig.7c). Furthermore, SAHA showed significant inhibitory effects on most EBV-encoded genes in tumor tissues (Fig.7d). Finally, we collected samples from organs at 30 days after inoculation and performed EBER ISH. EBER-positive cells were detected in the organs of control mice, but not SAHA-treated mice (Fig.7e). In the spleen, liver and lung, EBER-positive cells were sporadically observed in focal lesions, indicating hematogenous dissemination of tumor cells. Conversely, the expansion of EBER-positive cells from the renal capsule to parenchyma was observed in the kidney, indicating direct invasion. These results indicated that SAHA inhibited metastasis and invasion of lymphoma cells.


Anti-tumor effects of suberoylanilide hydroxamic acid on Epstein-Barr virus-associated T cell and natural killer cell lymphoma.

Siddiquey MN, Nakagawa H, Iwata S, Kanazawa T, Suzuki M, Imadome K, Fujiwara S, Goshima F, Murata T, Kimura H - Cancer Sci. (2014)

Suberoylanilide hydroxamic acid (SAHA) inhibits tumor growth and metastasis of Epstein–Barr virus (EBV)-positive natural killer (NK) cell lymphoma. (a) SNK6 cells (1 × 106 per mouse) were inoculated subcutaneously into NOG mice. Mice were treated with 100 mg/kg SAHA or DMSO (control) daily from days 4 to 28. Tumor sizes were measured twice per week. (b) At 30 days after inoculation, mice were killed, and Epstein–Barr virus-encoded small RNA-positive cells were detected by in situ hybridization in tumor tissues of SAHA-treated or control mice (scale bars: 200 μm). (c) At 30 days after inoculation, peripheral blood was collected, and plasma was separated. EBV-DNA was quantified by real-time PCR. (d) At 30 days, EBV-related gene expression in tumor tissues was quantified. β2-Microglobulin was used for relative quantification and assigned an arbitrary value of 1 (100). (e) EBER-positive cells, which meant EBV-positive lymphoma cells, were detected by in situ hybridization in organ tissues of SAHA-treated or control mice (scale bars: 200 μm). *P < 0.05, **P < 0.01, ***P < 0.002 by Mann–Whitney U-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317897&req=5

fig07: Suberoylanilide hydroxamic acid (SAHA) inhibits tumor growth and metastasis of Epstein–Barr virus (EBV)-positive natural killer (NK) cell lymphoma. (a) SNK6 cells (1 × 106 per mouse) were inoculated subcutaneously into NOG mice. Mice were treated with 100 mg/kg SAHA or DMSO (control) daily from days 4 to 28. Tumor sizes were measured twice per week. (b) At 30 days after inoculation, mice were killed, and Epstein–Barr virus-encoded small RNA-positive cells were detected by in situ hybridization in tumor tissues of SAHA-treated or control mice (scale bars: 200 μm). (c) At 30 days after inoculation, peripheral blood was collected, and plasma was separated. EBV-DNA was quantified by real-time PCR. (d) At 30 days, EBV-related gene expression in tumor tissues was quantified. β2-Microglobulin was used for relative quantification and assigned an arbitrary value of 1 (100). (e) EBER-positive cells, which meant EBV-positive lymphoma cells, were detected by in situ hybridization in organ tissues of SAHA-treated or control mice (scale bars: 200 μm). *P < 0.05, **P < 0.01, ***P < 0.002 by Mann–Whitney U-test.
Mentions: We subcutaneously inoculated 1 × 106 SNK6 cells into NOG mice. All of the mice developed tumors at the site of inoculation. Four days after the inoculation, mice were treated with SAHA daily up to day 28. The treated mice normally tolerated SAHA without showing any obvious toxicity. During this period, no significant difference in the body weights of SAHA-treated and control mice was noted (data not shown). Until the end of the experiment, the size of tumors in SAHA-treated mice increased gradually, but the tumor volume was significantly less than the control group (Fig.7a). EBER ISH showed the extent of the tumor in each mouse (Fig.7b). In the SAHA-treated mouse, the tumor was regressed with degeneration. Additionally, SAHA-treated mice showed a significantly lower plasma EBV-DNA level (Fig.7c). Furthermore, SAHA showed significant inhibitory effects on most EBV-encoded genes in tumor tissues (Fig.7d). Finally, we collected samples from organs at 30 days after inoculation and performed EBER ISH. EBER-positive cells were detected in the organs of control mice, but not SAHA-treated mice (Fig.7e). In the spleen, liver and lung, EBER-positive cells were sporadically observed in focal lesions, indicating hematogenous dissemination of tumor cells. Conversely, the expansion of EBER-positive cells from the renal capsule to parenchyma was observed in the kidney, indicating direct invasion. These results indicated that SAHA inhibited metastasis and invasion of lymphoma cells.

Bottom Line: Recent studies have reported that histone deacetylase (HDAC) inhibitors exert anticancer effects against various tumor cells.In addition, SAHA increased the expression of EBV-lytic genes and decreased the expression of EBV-latent genes.SAHA displayed a marked suppressive effect against EBV-associated T and NK cell lymphomas through either induction of apoptosis or cell cycle arrest, and may represent an alternative treatment option.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Show MeSH
Related in: MedlinePlus