Silencing of mTOR Facilitates the Cyclophosphamide-Mediated Cytotoxicity in Acute Lymphoblastic Leukemia

Abstract

Background: Acute lymphoblastic leukemia (ALL) is a neoplastic disorder in which lymphoid progenitors of patients proliferate malignantly and accumulate in peripheral blood (PB), bone marrow (BM), and other sites. According to several studies, the mammalian target of rapamycin (mTOR), which mediates several biological processes in cells, including cell survival, autophagy, cell polarization, etc, is highly involved in cancer progression, chemoresistance, and relapse. Several studies have shown that mTOR is hyper-activated in ALL cells. Also, its inhibition is associated with a better response to several anticancer drugs. Methods: In this study, the effect of mTOR inhibition along with cyclophosphamide treatment (an alkylating agent used for the treatment of several malignancies) was evaluated. In the current research, peripheral blood and bone marrow mononuclear cells from eleven ALL patients were treated with anti-mTOR siRNA (transfection by Lipofectamine) and cyclophosphamide. The efficacy of mTOR inhibition was evaluated by qRT-PCR. Next, the effect of different treatments was assessed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. Results: The findings demonstrated that the mTOR mRNA level was significantly reduced in leukemic cells when treated with mTOR siRNA-lipofectamine. Moreover, silencing mTOR considerably sensitized cells to cyclophosphamide. Cells treated with both cyclophosphamide and mTOR siRNA demonstrated the highest level of apoptosis. Conclusion: Based on the results achieved from the cytotoxicity test, we found that mTOR inhibition has a synergistic effect with cyclophosphamide treatment in ALL. Therefore, this combination therapy can be a promising approach for treating ALL, which should be examined more in subsequent investigations.

Keywords

• all
• cyclophosphamide
• mtor
• leukemia
• sirna
• chemoresistance