We investigated the anti-tumour effects and the underlying molecular mechanisms of a new oral histone deacetylase inhibitor (HDACi), chidamide, in NK/T cell lymphoma (NKTCL), a rare and highly aggressive non-Hodgkin lymphoma with poor outcomes. SNT-8 and SNK-10 NKTCL cell lines were exposed to different concentrations of chidamide for the indicated time. The treated cells were analysed for cell proliferation, cell cycle progression, and cell apoptosis. Proteins in the AKT/mTOR and MAPK signalling pathways and the DNA damage response (DDR) cell cycle checkpoint pathway were measured by Western blotting. Chidamide inhibited cell proliferation in a dose- and time-dependent manner, arrested cell cycle progression at the G0/G1 phase, and induced apoptosis in the NKTCL cell lines. In addition, we found that chidamide suppressed the phosphorylation levels of proteins in the AKT/mTOR and MAPK signalling pathways and activated the DDR cell cycle checkpoint pathway, that is, the ATM-Chk2-p53-p21 pathway. Expression of EBV genes was also assessed by Real-Time PCR. Chidamide induced EBV lytic-phase gene expression in EBV-positive NKTCL. Our results provide evidence that chidamide shows antitumour effects by inhibiting the AKT/mTOR and MAPK signalling pathways and activating the ATM-Chk2-p53-p21 signalling pathway in vitro.
Background: Extranodal NK/T cell lymphoma (NKTCL) is a highly aggressive non-Hodgkin lymphoma with poor prognosis. Resveratrol (RSV, 3,5,4′-trihydroxystilbene), a natural nontoxic phenolic compound found in the skin of grapes and some other spermatophytes, performs multiple bioactivities, such as antioxidant activity, anti-aging activity, reduction of cardiovascular disease risk and anticarcinogenic effect. Here we report the anti-tumor effect of RSV in NKTCL cell lines SNT-8, SNK-10 and SNT-16. Results: RSV inhibited NKTCL cell proliferation in a dose-and time-dependent manner and arrested cell cycle at S phase. It induced NKTCL cells apoptosis through mitochondrial pathway, shown as down-regulation of MCl-1 and survivin, up-regulation of Bax and Bad, and activation of caspase-9 and caspase-3. In addition, we found that RSV suppressed the phosphorylation level of AKT and Stat3, and activated DNA damage response (DDR) pathway directly or through up-regulation of Zta of Epstein-Barr virus (EBV). Furthermore, using KU55933 as the inhibitor of pATM, we verified that DDR played an important role in RSV inducing NKTCL apoptosis. RSV also showed synergistic effect on activating DDR pathway in combination with etoposide or ionizing radiation, which resulted in cell proliferation inhibition and apoptosis.
The long-lived, antigen-specific memory CD4 T cells, rather than PBMCs or peripheral lymphocytes, might be the ideal T cell subset candidates for analyzing the endotype of asthma. Memory CD4 T cells exhibiting a shift in STAT phosphorylation and specific cytokine-releasing profiles have the potential to facilitate the understanding of disease heterogeneity and severity, allowing the more personalized treatment of patients.
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