E3330 Enhanced Antitumor Effect of Adrinmycin on Human Extranodal Nasal-Type NK/T Cell Lymphoma Xenografted–Nude Mice

Extranodal Nasal-Type NK/T Cell Lymphoma (EN-NK/T-L) is a distinct clinicopathological entity of non-Hodgkin's lymphoma, which is characterized by a highly aggressive clinical process and poor prognosis especially when disseminated or recurrent after radiotherapy. Human purinic/apyrimidinic endonuclease/redox factor-1 (hAPE/Ref-1) is a multifunctional protein involved in the repair of DNA damaged by oxidative. Because of its involvement in DNA repair and apoptosis-related signaling mechanisms, APE/Ref-1 is also being discussed as a novel target for tumor-therapeutic approaches. In studies, high level of APE1 expression is associated with an resistance to chemotherapeutic agents and adverse prognosis. And recent studies show that E3330, a small molecule inhibitor of the Ape-1/Ref-1 redox domain, induce inhibition of growth in cancer cell in vitro by specific inhibiting the function of APE/REF-1. E3330 blocks the in vitro growth of pancreatic cancer-associated endothelial cells(J Cell Physiol. 2009 Apr;219(1):209–18.) and of the NK/T-cell lineage in our sdudy already and provides a potential therapeutic strategy in tumor. Thus far, no study has reported the experimental research on E3330 combined with chemotherapy in treating NK/T cell lymphoma. Therefore, we try to establish xenografted-nude mice model of human extranodal nasal type NK/T cell lymphoma and to investigate the effect of E3330 combined with adrinmycin on the human EN-NK/T-L xenografted-nude mice and its mechanism. Methods: EN-NK/T-L Xenografted-nude mice model was established by intraperitoneal injection of NK/T cell lymohoma cells SNK-6. IC50 of E3330 for SNK-6 was calculated according to the result of MTT assay. Xenografted- nude mice were divided into four groups: Control group were given equal volume sodium,po,d1-7□ G E3330 group were given E3330, 6mg/kg, po, d1-7□ GADM group were given ADM, 0.5mg/kg, ip,d1,4,7□ GE3330 + ADM group were given both E3330 and ADM, E3330, 6mg/kg, po, d1-7, ADM 0.5mg/kg, ip, D1,4,7. The tumor weight and the survival rate of tumor–bearing mice were assayed, the apoptosis cells were determined by TdT-mediated Dutp Nick-end-Labeling(Tunel). Immunohistochemistry were used to study the expression of ki-67. Immunofluorescence were used to study the expression of APE/REF-1. Results: Nude mice model of human extranodal nasal type NK/T cell lymphoma was established successfully. The results showed that the expression level of APE/REF-1 was higher in tumor tissues compared with that in normal tissues (Fig 1 A 1B). The transplanted tumor volumes of mice were significantly smaller in E3330 + ADM group than those in other three groups(p<0.05)(Table 1). The expression of ki-67 in E3330 + ADM group was lower than other groups(p<0.05) (Fig 2 A 2B 2C 2D) and the apoptosis cells were increased in the same group (Table 2). Conclusion: Our study showed that E3330 + adrinmycin can significantly inhibit the growth of transplanted tumor of extranodal nasal type NK/T cell lymphoma Xenografted-nude mice.

No relevant conflicts of interest to declare.