YM155 induces apoptosis in p53-deficient T-acute lymphoblastic leukemia cells independent of survivin inhibition

Abstract

T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from the malignant transformation of T-cell progenitors. Despite the significant progress in current treatment, challenges remain the lifelong morbidity after current chemotherapy regimens and postrelapse survival. In addition, patients with T-ALL have inferior outcomes compared with those with B-cell precursor; consequently, novel therapeutic approaches are still necessary to improve the outcome in this cohort. YM155 is an imidazolium derivative originally discovered as a suppressant of survivin expression. It has been reported that YM155 has potent antiproliferative activity on a variety of human cancer cell lines; however, its effects in T-ALL cells have been underexplored. The aim of the present study was to examine the effects of YM155 on p53-deficient T-ALL cell lines, JURKAT and CCRF-CEM. Resazurin dye was used to evaluate cell viability. Colony formation was observed in MethoCult methylcellulose medium. Apoptotic cells were detected by flow cytometry (annexin V labeling and TUNEL assay). Cell cycle analysis was carried out by DNA quantification in flow cytometry. DNA damage was assessed using a comet assay and the survivin expression profile was evaluated by real-time PCR and immunoblotting. YM155 treatment decreased cell viability and clonogenicity capacity of T-ALL cells, increased the apoptosis index and DNA damage, and altered the cell cycle dynamic, independent of survivin inhibition. Taken together, the data reinforce that YM155 may be useful as a therapeutic possibility to combat leukemia.

Effect of Sepatronium Bromide (YM-155) on DNA Double-Strand Breaks Repair in Cancer Cells

“…These results suggest that survivin cannot be the only target of YM-155, and the observed sensitizing effect should be survivin-independent [32]. The same surprising survivin expression-independent effect of YM-155 was also reported for p53-deficient T-acute lymphoblastic leukemia (ALL) [33] and renal cell carcinoma [34]. Another study evaluating the radiosensitization effects of YM-155 on esophageal squamous cell carcinoma reported that the treatment abrogated the radiation-induced G2/M arrest [35].…”

Non-cytotoxic 1,2,3-triazole tethered fused heterocyclic ring derivatives display Tax protein inhibition and impair HTLV-1 infected cells

“…27 For instance, a range of plant extracts have been tested by this method to isolate components with potent inhibitory activity for further tests, 28,29 and YM155, an antitumor imidazolium compound and potent inhibitor of Survivin, was tested on a variety of human cancer cell lines, including T-acute lymphoblastic leukemia (T-ALL). 30 The initial screening on HTLV-1-infected cell line (MT-2) led us to select eight compounds (02, 05, 06, 13, 15, 21, 22 and 25) (Figure 2) for further studies as they significantly reduced the metabolic activity of the cells (≥ 70%) in a similar manner to the positive control (ETO). In a follow-up experiment, we investigated whether the selected compounds could interfere in the cell cycle and induce apoptosis of MT-2 cell line.…”

Benzophenone Derivatives Showed Dual Anti-Inflammatory and Antiproliferative Activities by Inhibiting COX Enzymes and Promote Cyclin E Downregulation

“…Cell viability was assessed in tumor and normal cells according to well-established protocols. 40,41 Cells were seeded into 96-well flat-bottom plates at a density of 5 ×10 3 cells well -1 or 1 ×10 4 cells well -1 depending on the cell line. Cell cultures were treated with substances 4 or 5 (concentration range 0-500 µM) for 48 h. Ketoprofen and cisplatin (Sigma-Aldrich, Saint Louis, MO, USA) were used as controls.…”