Src family kinase inhibitor bosutinib enhances retinoic acid-induced differentiation of HL-60 leukemia cells

Leuk Lymphoma. 2018 Dec;59(12):2941-2951. doi: 10.1080/10428194.2018.1452213. Epub 2018 Mar 23.

Abstract

The acute promyelocytic leukemia (APL) has been treated with all-trans retinoic acid (RA) for decades. While RA has largely been ineffective in non-APL AML subtypes, co-treatments combining RA and other agents are currently in clinical trials. Using the RA-responsive non-APL AML cell line HL-60, we tested the efficacy of the Src family kinase (SFK) inhibitor bosutinib on RA-induced differentiation. HL-60 has been recently shown to bear fidelity to a subtype of AML that respond to RA. We found that co-treatment with RA and bosutinib enhanced differentiation evidenced by increased CD11b expression, G1/G0 cell cycle arrest, and respiratory burst. Expression of the SFK members Fgr and Lyn was enhanced, while SFK activation was inhibited. Phosphorylation of several sites of c-Raf was increased and expression of AhR and p85 PI3K was enhanced. Expression of c-Cbl and mTOR was decreased. Our study suggests that SFK inhibition enhances RA-induced differentiation and may have therapeutic value in non-APL AML.

Keywords: Retinoic acid; SFK inhibitors; leukemia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aniline Compounds / pharmacology*
  • Aniline Compounds / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Differentiation / drug effects*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology
  • Nitriles / pharmacology*
  • Nitriles / therapeutic use
  • Quinolines / pharmacology*
  • Quinolines / therapeutic use
  • Signal Transduction / drug effects
  • Tretinoin / pharmacology*
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism

Substances

  • Aniline Compounds
  • Nitriles
  • Quinolines
  • bosutinib
  • Tretinoin
  • src-Family Kinases