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This study investigated the cytotoxic effect of oridonin (ORI), a diterpenoid isolated from Rabdosia rubescens, in human diffuse large B cell lymphoma (DLBCL) in vitro and in vivo and the potential molecular mechanisms for ORI-induced cell apoptosis. ORI treatment caused reactive oxygen species (ROS)-mediated oxidative DNA damage response (DDR) and the c-Jun N-terminal kinase (JNK) pathway activation, leading to an induction of intrinsic apoptosis. ROS abolition blocked ORI-induced apoptosis and attenuated the expression of phospho-histone H2AX and phospho-JNK, indicating that ROS-mediated DNA damage and JNK pathway activation were involved in ORI-induced apoptosis. The systemic administration of ORI suppressed the growth of human DLBCL xenografts without showing significant toxicity. These findings suggest that ORI may have promising therapeutic application in DLBCL.

To assess the relevance of C-X-C chemokine receptor type 4 (CXCR4) and mammalian target of rapamycin (mTOR) to large-B-cell lymphoma (DLBCL), levels of protein expression were measured in 56 DLBCL patients who had received rituximab-based therapy. Of these, 34 were positive for CXCR4 expression (60.7%) and 31 for mTOR (55.4%). CXCR4 expression was positively correlated with mTOR expression (r = 0.602; p = .000). CXCR4 expression was significantly associated with high lactate dehydrogenase (LDH) level (p = .009), high IPI score (p = .030) and non-GCB subtype (p = .006). Furthermore, the expression levels of CXCR4 and mTOR were negatively correlated with the chance of remission (p .05). Kaplan-Meier analysis indicated significantly shorter progression-free survival (PFS) and overall survival (OS) in patients positive for CXCR4 and mTOR expression. The combination therapy with CXCR4 inhibitor WZ811 and mTOR inhibitor everolimus showed syncergistic effect in DLBCL cell lines. These results suggest that the expression of CXCR4 and mTOR may be suitable as biomarkers of the prognosis of DLBCL and for development of new therapeutic strategies.

We evaluated the efficacy of the anti-CD20 monoclonal antibody rituximab in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus for treating diffuse large B-cell lymphoma (DLBCL). The combination of rituximab and everolimus was more effective for inhibiting cell growth compared with single-agent therapy. An increase in G0/G1 cell cycle arrest and an increased population of cells in apoptosis were observed in the combination treatment group. The addition of rituximab reduced the overexpression of p-AKT caused by the negative feedback loop of everolimus and had an enhanced effect on inhibition of mTOR signaling, thus providing a rationale for this synergistic effect. Furthermore, combination treatment was also more effective than treatment with either agent alone for inhibiting the growth of DLBCL xenografts. Our study provides preclinical evidence and a theoretical basis for combination therapy with rituximab and everolimus in DLBCL.

We demonstrate the synergistic antitumor effect of oridonin and the PI3K/mTOR inhibitor NVP-BEZ235 on the non-germinal center B cell-like subtype of diffuse large B cell lymphoma (non-GCB DLBCL) both in vitro and in vivo. The underlying mechanism may be multifunctional, involving apoptosis, AKT/mTOR and NF-kB inactivation, and ROS-mediated DNA damage response. Our findings pave the way for a new potential treatment option for non-GCB DLBCL with the combination of oridonin and NVP-BEZ235. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0303-0) contains supplementary material, which is available to authorized users.

Diffuse large B cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma and accounts for approximately 30 % of newly diagnosed lymphoid neoplasms in Western countries, and 40–50 % in China. A better understanding of the biology of DLBCL is needed for the development of potential therapeutic agents that target specific intracellular pathways. In this study, expression of the important components of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway and their clinical significance were investigated in 73 DLBCL cases. The effect of rituximab alone or combined with the PI3K/AKT/mTOR pathway inhibitor rapamycin was further evaluated in the DLBCL cell lines. A total of 73 patients were identified, including 45 men and 28 women aged 18 to 78 years (median age 50 years). Of these patients, p-AKT was positive in 40 cases (54.8 %), p-p70S6K in 34 cases (46.6 %), and p-4E-BP1 in 33 cases (45.2 %). Activation of the PI3K/AKT/mTOR pathway was related to poor disease outcome in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) but not in those treated with rituximab-CHOP. Rituximab combined with rapamycin synergically downregulated the PI3K/AKT/mTOR signaling pathway. Western blot analysis revealed a baseline activation status of the PI3K/AKT/mTOR pathway in DLBCL cell lines, with high levels of p-AKT, p-mTOR, in addition to downstream molecules p-p70S6K and p-4E-BP1. The results indicate that the PI3K/AKT/mTOR pathway is a potentially important signaling route and an unfavorable prognostic factor for DLBCL. Patients with PI3K/AKT/mTOR activation experience a more rapidly deteriorating clinical course with poor treatment response and decreased survival time. Addition of rituximab could downregulate PI3K/AKT/mTOR activation, reversing its negative effect on chemotherapy-treated patients. In addition, our results indicate that the combination of rituximab and inhibition of the activated PI3K/AKT/mTOR pathway could be a promising target for DLBCL therapeutic intervention in the future.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with recognised variability in molecular aetiology and clinical outcome. Though the use of agents such as rituximab significantly improves outcome, intrinsic genetic and morphological factors greatly affect the response to treatment. The objective of this study was to evaluate the prognostic value of immunohistochemical subtyping and the International Prognostic Index (IPI) for predicting treatment outcome in Chinese DLBCL patients. We followed 108 cases of DLBCL and performed prognostic analyses based on molecular subtyping of the disease through immunostaining of tissue samples. The use of rituximab conferred a clinical benefit to DLBCL patients regardless of disease subtype. Importantly, this treatment regimen also improved outcomes in patients with the non-germinal centre B-cell-like (GCB) DLBCL subtype, frequently associated with poorer prognosis. Our results suggest that IPI was the best tool for the prediction of treatment outcome in our patient cohort, regardless of treatment regimen. Furthermore, the use of rituximab alongside classical chemotherapy regimens can improve the outcomes for DLBCL patients who exhibit both GCB and non-GCB subtypes of the disease.

Abstract 1934 Poster Board I-957 A better understanding of the biology of diffuse large B cell lymphoma(DLBCL) is needed in the developement of potential therapeutic agents that target specific intracellular pathway. In this study, expression of the important members of PI3K/Akt/mTOR signaling pathway and their clinical significance were investigated in 73 cases of DLBCL. Immunohistochemical analyses showed that activation of Akt and its downstream targets such as p-p70S6K, p-4E-BP1, YB-1 and Mcl-1 were present in DLBCL cases. Activation of PI3K/Akt/mTOR pathway was related to poor disease outcome in DLBCL patients treated by CHOP but not in those treated by R-CHOP. Rituximab combined with chemotherapy could down-regulate PI3K/Akt/mTOR activation and reverse its negative effect on chemotherapy-treated patients. The effect of Rituximab alone or combined with the mTOR inhibitor Rapamycin was further evaluated in DLBCL cell line SUDHL-4. Rituximab combined with Rapamycin possessed synergic effect in down-regulating PI3K/Akt/mTOR signaling pathway, inhibited proliferation and caused G1 arrest in DLBCL cell line. The results showed that PI3K/Akt/mTOR signaling pathway activation presented in DLBCL may be considered as a prognostic biomarker and a promising target for therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.