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Icaritin induces lytic cytotoxicity in extranodal NK/T-cell lymphoma.

Wu T, Wang S, Wu J, Lin Z, Sui X, Xu X, Shimizu N, Chen B, Wang X - J. Exp. Clin. Cancer Res. (2015)

Bottom Line: The anti-proliferative and pro-apoptotic effects of Icaritin are likely mediated by inhibition of Stat3 and Akt pathways through LMP1 downregulation.Importantly, Icaritin induces EBV lytic gene expression in ENKL cells, and the combination of Icaritin and the antiviral drug ganciclovir (GCV) is more effective in inducing ENKL cells apoptosis than Icaritin or GCV alone.These findings indicate that EBV-targeted approaches may have significant therapeutic potential for ENKL treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Huashan Hospital, Shanghai Medical College, Fudan University, 12 Urumqi Middle Road, 200040, Shanghai, China. wuting2011@163.com.

ABSTRACT

Background: Extranodal NK/T-cell lymphoma (ENKL) is an aggressive hematological malignancy associated with Epstein-Barr virus (EBV) infection. It is often resistant to conventional chemotherapy and has a poor prognosis. Icaritin, a compound derived from Chinese herbal medicine, Herba Epimedii, has been reported to exert antitumor effects on a variety of cancer cell lines. In the present study, we investigated the cytotoxic effects of Icaritin on the two EBV-positive ENKL cell lines SNK-10 and SNT-8, along with the underlying molecular mechanisms.

Methods: ENKL cell lines SNK-10 and SNT-8 were exposed to different concentrations of Icaritin for the indicated time. Treated cells were analyzed for cell proliferation, cell cycle, and cell apoptosis. Phosphorylation of Stat3 and Akt proteins in signaling pathways and the EBV-encoded LMP1 proteins were measured by Western blot. Expression of EBV genes was assessed by Real-Time PCR.

Results: Our results showed that Icaritin dose-dependently inhibits ENKL cell proliferation and induces apoptosis and cell cycle arrest at G2/M phase. Additionally, Icaritin upregulates Bax, downregulates Bcl-2 and pBad, and activates caspase-3 and caspase-9. The anti-proliferative and pro-apoptotic effects of Icaritin are likely mediated by inhibition of Stat3 and Akt pathways through LMP1 downregulation. Importantly, Icaritin induces EBV lytic gene expression in ENKL cells, and the combination of Icaritin and the antiviral drug ganciclovir (GCV) is more effective in inducing ENKL cells apoptosis than Icaritin or GCV alone.

Conclusions: These findings indicate that EBV-targeted approaches may have significant therapeutic potential for ENKL treatment.

No MeSH data available.


Related in: MedlinePlus

Icaritin induces cell cycle arrest at G2/M phase in ENKL cells. Cell cycle distribution of SNK-10 and SNT-8 cells was analyzed by flow cytometry with PI staining after 48 h treatment. A. Representative flow cytometry histograms. B. Cell distribution at G0/G1, S, and G2/M phases of the cell cycle (n = 3). *p < 0.05, #p < 0.01 vs control.
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Fig2: Icaritin induces cell cycle arrest at G2/M phase in ENKL cells. Cell cycle distribution of SNK-10 and SNT-8 cells was analyzed by flow cytometry with PI staining after 48 h treatment. A. Representative flow cytometry histograms. B. Cell distribution at G0/G1, S, and G2/M phases of the cell cycle (n = 3). *p < 0.05, #p < 0.01 vs control.

Mentions: We evaluated the effects of Icaritin on cell cycle distribution of SNK-10 and SNT-8 by flow cytometry with PI staining. Our data showed that Icaritin treatment significantly increased the proportion of cells at G2/M phase, which was accompanied by a decreased proportion at S phase (Figure 2). Specifically, untreated SNK-10 and SNT-8 cells had only 3.5% and 0.6% cells, respectively, at G2/M phase. Treatment of SNK-10 and SNT-8 cells with 50 μM and 32 μM Icaritin significantly increased the proportion of cells at G2/M phase to 22.4% and 24.1%, respectively. Moreover, while untreated SNK-10 and SNT-8 cells had 63.7% and 56.7% cells at S phase, respectively, treatment with 50 μM and 32 μM Icaritin significantly reduced the proportion of cells at S phase to 42.2% and 36.5%, respectively (Figure 2B). These results suggested that Icaritin inhibits ENKL cell proliferation through inducing cell cycle arrest at G2/M phase.Figure 2


Icaritin induces lytic cytotoxicity in extranodal NK/T-cell lymphoma.

Wu T, Wang S, Wu J, Lin Z, Sui X, Xu X, Shimizu N, Chen B, Wang X - J. Exp. Clin. Cancer Res. (2015)

Icaritin induces cell cycle arrest at G2/M phase in ENKL cells. Cell cycle distribution of SNK-10 and SNT-8 cells was analyzed by flow cytometry with PI staining after 48 h treatment. A. Representative flow cytometry histograms. B. Cell distribution at G0/G1, S, and G2/M phases of the cell cycle (n = 3). *p < 0.05, #p < 0.01 vs control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4336495&req=5

Fig2: Icaritin induces cell cycle arrest at G2/M phase in ENKL cells. Cell cycle distribution of SNK-10 and SNT-8 cells was analyzed by flow cytometry with PI staining after 48 h treatment. A. Representative flow cytometry histograms. B. Cell distribution at G0/G1, S, and G2/M phases of the cell cycle (n = 3). *p < 0.05, #p < 0.01 vs control.
Mentions: We evaluated the effects of Icaritin on cell cycle distribution of SNK-10 and SNT-8 by flow cytometry with PI staining. Our data showed that Icaritin treatment significantly increased the proportion of cells at G2/M phase, which was accompanied by a decreased proportion at S phase (Figure 2). Specifically, untreated SNK-10 and SNT-8 cells had only 3.5% and 0.6% cells, respectively, at G2/M phase. Treatment of SNK-10 and SNT-8 cells with 50 μM and 32 μM Icaritin significantly increased the proportion of cells at G2/M phase to 22.4% and 24.1%, respectively. Moreover, while untreated SNK-10 and SNT-8 cells had 63.7% and 56.7% cells at S phase, respectively, treatment with 50 μM and 32 μM Icaritin significantly reduced the proportion of cells at S phase to 42.2% and 36.5%, respectively (Figure 2B). These results suggested that Icaritin inhibits ENKL cell proliferation through inducing cell cycle arrest at G2/M phase.Figure 2

Bottom Line: The anti-proliferative and pro-apoptotic effects of Icaritin are likely mediated by inhibition of Stat3 and Akt pathways through LMP1 downregulation.Importantly, Icaritin induces EBV lytic gene expression in ENKL cells, and the combination of Icaritin and the antiviral drug ganciclovir (GCV) is more effective in inducing ENKL cells apoptosis than Icaritin or GCV alone.These findings indicate that EBV-targeted approaches may have significant therapeutic potential for ENKL treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Huashan Hospital, Shanghai Medical College, Fudan University, 12 Urumqi Middle Road, 200040, Shanghai, China. wuting2011@163.com.

ABSTRACT

Background: Extranodal NK/T-cell lymphoma (ENKL) is an aggressive hematological malignancy associated with Epstein-Barr virus (EBV) infection. It is often resistant to conventional chemotherapy and has a poor prognosis. Icaritin, a compound derived from Chinese herbal medicine, Herba Epimedii, has been reported to exert antitumor effects on a variety of cancer cell lines. In the present study, we investigated the cytotoxic effects of Icaritin on the two EBV-positive ENKL cell lines SNK-10 and SNT-8, along with the underlying molecular mechanisms.

Methods: ENKL cell lines SNK-10 and SNT-8 were exposed to different concentrations of Icaritin for the indicated time. Treated cells were analyzed for cell proliferation, cell cycle, and cell apoptosis. Phosphorylation of Stat3 and Akt proteins in signaling pathways and the EBV-encoded LMP1 proteins were measured by Western blot. Expression of EBV genes was assessed by Real-Time PCR.

Results: Our results showed that Icaritin dose-dependently inhibits ENKL cell proliferation and induces apoptosis and cell cycle arrest at G2/M phase. Additionally, Icaritin upregulates Bax, downregulates Bcl-2 and pBad, and activates caspase-3 and caspase-9. The anti-proliferative and pro-apoptotic effects of Icaritin are likely mediated by inhibition of Stat3 and Akt pathways through LMP1 downregulation. Importantly, Icaritin induces EBV lytic gene expression in ENKL cells, and the combination of Icaritin and the antiviral drug ganciclovir (GCV) is more effective in inducing ENKL cells apoptosis than Icaritin or GCV alone.

Conclusions: These findings indicate that EBV-targeted approaches may have significant therapeutic potential for ENKL treatment.

No MeSH data available.


Related in: MedlinePlus