Abstract
Purpose: Sepantronium bromide (YM155) is a Survivin inhibitor which recently advanced as an anticancer agent in phase II clinical trials. Survivin belongs to IAP (inhibitor of apoptosis) gene family and is a pivotal target for treatment due to its overexpression and oncogenic function in many malignancies, including acute lymphoblastic leukemia (ALL). Although survivin is a specific target for YM155, recent reports have shown that it has many other crucial targets that regulate its anti-apoptotic effects. The aim of this study was to investigate whether YM155 could have an effect on cell death-inducing genes as well as inducing apoptosis in T-ALL MOLT4- cell line. Methods: We treated MOLT-4 cells with increasing concentrations of YM155 and then cell viability was determined using MTT (methyl thiazolyl tetrazolium) assay. Also, the rate of induction of apoptosis in MOLT-4 cells and the target genes expression levels were evaluated by Annexin V/PI and real-time PCR, respectively. Results: YM155 inhibited cell growth in MOLT-4 cells. This outcome is achieved by inducing apoptosis and a significant increase in the expression level of P53, MiR-9, caspase 3 and decreasing the mRNA expression levels of survivin, Sirtuin1(SIRT1), member of anti-apoptotic proteins family (Bcl-2), and epithelial-to-mesenchymal transition (EMT) initiating factors Snail1and Zeb2. Conclusion: The results showed that use of YM155 can be a potential drug therapy in T-ALL patients with promising effects on apoptosis induction.
Highlights
Acute lymphoblastic leukemia )acute lymphoblastic leukemia (ALL)) is one of the most common variants of leukemia, which affects all ages, with high costs and treatment failure.[1]
A whole transcription study on MDAMB-231 cells after YM155 treatment documented that this drug changed the expression pattern of micro-RNAs such as miR-125b-1.19 In the present study, we studied the role of YM155 on the induction of apoptosis and gene expression associated with the cell death and apoptosis; we defined the expression of miR-9 as an important regulator of gene expression in T-ALL MOLT4 cell line
YM155 increased miR-9 and decreased survivin, Bcl-2 and genes related to epithelial-to-mesenchymal transition (EMT) and DNA repair expression level We used a qRT-PCR to evaluate survivin and several other candidate genes along with miR9- expression in MOLT-4 cells treated with YM155 (1.82 mM) for 24 hours
Summary
Acute lymphoblastic leukemia )ALL) is one of the most common variants of leukemia, which affects all ages, with high costs and treatment failure.[1] the diagnosis and treatment of these malignancies nowadays have greatly improved, the overall survival rate of patients is still low.[2] in order to reduce the therapeutic burden, target therapy in ALL patients seems essential. For this reason, in recent clinical and preclinical studies, many targets have been tested for effective treatment.[2]. 2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro1H-naphtho [2,3-d] is a pioneer chemical compound with significant therapeutic effects, which has been shown to induce apoptosis, inhibit invasion and suppress drug resistance in numerous cancer cell lines.[3,4,5,6,7,8] YM155 has been shown to be tolerable in phase II clinical trials in patients with melanoma[8] and advanced refractory NSCLS.[9]
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