Synergistic Lethality with Gemcitabine and Arsenic Trioxide Against Human T Cell Lymphoma Jurkat Cells

Abstract There is still lack suitable agent that significantly changes the poor prognoses of T-cell non-Hodgkin's lymphoma (NHL), so that part of the patients who are far beyond the standard of first-line could not received effective treatment, therefore, it is urgent that seeking for a salvage treatment for patients with refractory malignant lymphoma, our destination is combination strategy aimed to higher anti-tumor activity with lower toxicity.

GEM is a deoxycytidine analog with anti-metabolite activity in tumors through destroying the replication of cells and inhibiting ribonucleotide reductase as a prodrug. Recently, many clinical trials show that gemcitabine alone or in combination with other chemotherapy drugs can improve overall response rate and survival outcomes in malignant lymphoma patients compared with other chemotherapy regimens, such as vinorelbine and liposomal doxorubicin, busulfan and melphalan, which are active agents in all types of malignant lymphoma.

ATO as a traditional medicine has been evaluated its good efficacy in a variety of hematologic malignancies, including myeloproliferative diseases, multiple myeloma, lymphoma. Currently, many clinical trials represented that the addition of ATO to standard treatment regimens can improve survival outcomes and may allow a reduction in cytotoxic chemotherapy exposure in other malignancies. The basis of related research found that ATO play killing effect on the cancer cells through multiple apoptotic pathways and many mechanisms. ATO was shown to bear relevant cytotoxic activity on lymphoma cell lines. The safety profile of ATO for the effective treatment and its toxicity is easily under control, which make it a preferred solution for combined chemotherapy scheme.

Thus, in this study we found that the combination of ATO and GEM can lead to synergistic the cytotoxic effect, exert an enhanced effect on inhibiting Akt signaling and Bcl-2, up-regulating cleaved caspase-3, and inhibit the cell proliferation and self-renewal ability, and induce G₀/G₁ cell cycle arrest and apotosis in Jurkat cells, which provide preclinical evidence and a theoretical basis for combination therapy with ATO and GEM as a salvage therapy in treating relapsed or refractory aggressive non-Hodgkin's lymphoma.