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

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
• leukemia
• SFK inhibitors

Acknowledgements

This work was supported by grant R01 CA152870 from the National Institutes of Health (AY) and by the Center on the Physics of Cancer Metabolism through Award Number 1U54CA210184-01 from the National Cancer Institute.

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The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2018.1452213.