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

Abstract

BackgroundExtranodal 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.MethodsENKL 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.ResultsOur 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.ConclusionsThese findings indicate that EBV-targeted approaches may have significant therapeutic potential for ENKL treatment.

Therapies based on targeting Epstein‐Barr virus lytic replication for EBV‐associated malignancies

“…It has been demonstrated that etoposide causes EBV reactivation in Akata cells . Icaritin induces the expression of EBV lytic genes by inhibiting the LMP1‐mediated STAT3 and Akt pathways . Rituximab and dexamethasone synergistically induce lytic EBV infection, rendering EBV‐positive lymphoma cells more susceptible to GCV cytotoxicity in vitro and in vivo .…”

Down-regulation of microRNA-10a mediates the anti-tumor effect of icaritin in A549 cells via the PTEN/AKT and ERK pathway

“…Icaritin is a prenylflavonoid derivative from a traditional Chinese herb, Epimedium Genus. Recently, accumulating studies have demonstrated an anti-tumor effect of icaritin in various cancers, including solid tumors and hematological cancers, such as lung cancer (Zheng et al 2014), hepatocel-lular carcinoma (Sun et al 2015;Hu et al 2016;Lu et al 2017), breast cancer (Guo et al 2011;Tiong et al 2012), esophageal cancer (Han et al 2018), glioblastoma Liu et al 2018), leukemia and lymphoma (Zhu et al 2011;Li et al 2013;Li et al 2014;Wu et al 2015;Zhu et al 2015;Yang et al 2019). Icaritin exerts its anti-tumor effects in various cancers mainly by inhibiting cell proliferation, inducing cell differentiation and apoptosis, suppressing cell migration and invasion (Zheng et al 2014;Xu et al 2015).…”

Lytic Induction Therapy against Epstein–Barr Virus-Associated Malignancies: Past, Present, and Future

“…Knockdown of STAT3 sensitized BL cells to lytic inducers for reactivation of lytic cycle, while STAT3 inhibition by small molecules, AG490, WP1066, or stattic was found to reactivate lytic cycle of EBV and enhance induction of lytic cycle in EBV-positive BL cells and LCLs by NaB or Aza [ 101 ]. Furthermore, icaritin inhibited STAT3 and AKT pathways by downregulating LMP1 expression, which consequently induced EBV lytic gene expression in ENKL cell lines [ 102 ]. In contrast, berberine was found to repress the level of EBNA1 by inhibiting EBNA1 promoter Qp.…”