Details

Autor(en) / Beteiligte

• Wahiduzzaman, Md
• Ota, Akinobu
• Karnan, Sivasundaram
• Hanamura, Ichiro
• Mizuno, Shohei
• Kanasugi, Jo
• Rahman, Md Lutfur
• Hyodo, Toshinori
• Konishi, Hiroyuki
• Tsuzuki, Shinobu
• Takami, Akiyoshi
• Hosokawa, Yoshitaka

Titel

Novel combined Ato-C treatment synergistically suppresses proliferation of Bcr-Abl-positive leukemic cells in vitro and in vivo

Ist Teil von

• Cancer letters, 2018-10, Vol.433, p.117-130

Ort / Verlag

Ireland: Elsevier B.V

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Chronic myelogenous leukemia (CML) accounts for 15–20% of all leukemias affecting adults. Despite recent advances in the development of specific Bcr-Abl tyrosine kinase inhibitors (TKIs), some CML patients suffer from relapse due to TKI resistance. Here, we assessed the efficacy of a novel combinatorial arsenic trioxide (ATO) and cisplatin (CDDP) treatment (Ato-C) in human Bcr-Abl-positive leukemic cells. Combination index analyses revealed that a synergistic interaction of ATO and CDDP elicits a wide range of effects in K562, KU-812, MEG-A2, and KCL-22 cells. Notably, Ato-C synergistically enhanced apoptosis and decreased the survival of both acquired TKI-resistant CML cells and the cells expressing mutant Bcr-AblT315I. In addition, Ato-C dramatically decreased the phosphorylation level of forkhead transcription factor FOXO1/3a and STAT5 as well as c-Myc protein level. Interestingly, results of gene set enrichment analysis showed that Ato-C significantly downregulates the expression of MYC- and/or E2F1-target genes. Furthermore, Ato-C significantly suppressed the proliferation of MEG-A2-derived tumor when compared with that following monotherapy in vivo. Collectively, these results suggest that combined Ato-C treatment could be a promising alternative to the current therapeutic regime in CML. [Display omitted] •ATO acts synergistically with CDDP to inhibit growth of TKI-resistant CML cells.•Ato-C (ATO/CDDP) substantially induces apoptosis of Ph + CML cells.•Ato-C significantly downregulates expression of MYC oncogenic signature.•Ato-C decreases phosphorylation level of FOXO transcriptional factor.•Ato-C significantly reduces tumor growth compared with either monotherapy in vivo.