ITR‑284 modulates cell differentiation in human chronic myelogenous leukemia K562 cells

Oncol Rep. 2018 Jan;39(1):383-391. doi: 10.3892/or.2017.6090. Epub 2017 Nov 9.

Abstract

ITR‑284 is a carboxamide analog that can inhibit proliferation in human promyelocytic leukemia HL-60 cells. To understand the effects and molecular mechanisms of ITR‑284 in human erythromyeloblastoid leukemia, we treated K562 cells with different concentrations of ITR‑284 (0, 2, 4, 6, 8 and 10 nM) and all-trans retinoic acid (ATRA) (0, 0.1, 0.5, 1, 5 and 10 µM) for 24 h. The IC50 of ITR‑284 was ~10 nM in K562 cells treated for 24 h as determined by MTT assay. May-Grünwald-Giemsa staining and nitro blue tetrazolium (NBT) assays were used to determine cell morphology changes and differentiation after ITR‑284 and ATRA treatment. In addition, mRNA expression levels of hematopoietic factors, including GATA‑1, NF-E2 and GATA‑2, were elevated, while expression levels of BCR‑ABL were downregulated in K562 cells after 24 h of treatment with ITR‑284 as determined by quantitative reverse transcription polymerase chain reaction. In addition, western blot analyses showed that FOXM1, GLI 1 and c-MYC protein levels were decreased by ITR‑284. Taken together, our data show that ITR‑284 induced K562 cell differentiation, which led to decreased tumorigenesis. Our findings suggest that ITR‑284 could be a potential candidate for treating chronic myelogenous leukemia.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Differentiation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Forkhead Box Protein M1 / metabolism
  • Fusion Proteins, bcr-abl / genetics
  • GATA1 Transcription Factor / genetics
  • GATA2 Transcription Factor / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Regulatory Networks / drug effects*
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • NF-E2 Transcription Factor, p45 Subunit / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Thiophenes / pharmacology*
  • Tretinoin / pharmacology
  • Zinc Finger Protein GLI1 / metabolism

Substances

  • Antineoplastic Agents
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • GATA1 Transcription Factor
  • GATA1 protein, human
  • GATA2 Transcription Factor
  • GATA2 protein, human
  • GLI1 protein, human
  • MYC protein, human
  • N-(2-dimethylaminoethyl)-4,8-dihydrobenzo(1,2-b,4,5-b')dithiophene-2-carboxamide
  • NF-E2 Transcription Factor, p45 Subunit
  • NFE2 protein, human
  • Proto-Oncogene Proteins c-myc
  • Thiophenes
  • Zinc Finger Protein GLI1
  • Tretinoin
  • Fusion Proteins, bcr-abl