Abstract
Background:Over-expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1 is associated with resistance to chemotherapeutic agents such as fludarabine. Moreover, an inverse relationship between miRNA-15a levels with Bcl-2 and Mcl-1 expression has been observed in CLL patients. In this study, the effect of miRNA-15a on apoptosis and sensitivity of the CLL cells to fludarabine was investigated. Methods:After treatments, the Mcl-1 and Bcl-2 expression levels were quantified by RT-qPCR. Trypan blue assay was used to explore the effects of miRNA-15a and fludarabine on cell proliferation. The cytotoxicity was measured using MTT assay and combination index analysis. Cell death was determined using cell death detection ELISA assay and caspase-3 activity assay Kits. Results:Results showed that miRNA-15a clearly decreased the mRNA levels of Bcl-2 and Mcl-1 in a time dependent manner, which led to CLL-II cell proliferation inhibition and enhancement of apoptosis (p < 0.05, relative to control). Transfection of the miRNA-15a synergistically reduced the cell survival rate and lowered the IC50 value of fludarabine. Furthermore, miRNA-15a significantly enhanced the apoptotic effect of fludarabine. Conclusions:Our data propose that suppression of Bcl-2 and Mcl-1 by miRNA-15a can effectively inhibit the cell proliferation and sensitize CLL cells to fludarabine. Therefore, miRNA-15a can be considered as a potential therapeutic target in CLL resistant patients.
Highlights
Chronic lymphocytic leukemia (CLL) is a haematological malignancy of B lymphocytes and the most prevalent type of leukemia in adults (Danilov, 2013; Khan and Siddiqi, 2018)
To analyze whether mRNA-15a could enhance the sensitivity of the CLL-CII leukemia cells to fludarabine, a combination treatment of miRNA-15a and fludarabine was investigated
It has been reported that genetic factors such as p53 dysfunction, deriving from 17p13 deletion, 11q22.3 deletion and immunoglobulin (Ig) V (H) unmutated status have been associated with fludarabine resistance (Ferracin et al, 2010)
Summary
Chronic lymphocytic leukemia (CLL) is a haematological malignancy of B lymphocytes and the most prevalent type of leukemia in adults (Danilov, 2013; Khan and Siddiqi, 2018). Fludarabine (9-b-D-arabinofuranosyl2-fluoroadenine), a purine nucleoside analog, is one of the most active single therapeutic agents in the treatment of CLL. Due to their potential to kill non-dividing cells, fludarabine produces good response and often is used as first and second-line treatment in CLL patients (Ferracin et al, 2010; Moussay et al, 2010). Results: Results showed that miRNA-15a clearly decreased the mRNA levels of Bcl-2 and Mcl-1 in a time dependent manner, which led to CLL-II cell proliferation inhibition and enhancement of apoptosis (p < 0.05, relative to control). Conclusions: Our data propose that suppression of Bcl-2 and Mcl-1 by miRNA-15a can effectively inhibit the cell proliferation and sensitize CLL cells to fludarabine. MiRNA-15a can be considered as a potential therapeutic target in CLL resistant patients
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