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.
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Authors | Robert J MacDonald, Rodica P Bunaciu, Victoria Ip, David Dai, David Tran, Jeffrey D Varner, Andrew Yen |
Journal | Leukemia & lymphoma
(Leuk Lymphoma)
Vol. 59
Issue 12
Pg. 2941-2951
(12 2018)
ISSN: 1029-2403 [Electronic] United States |
PMID | 29569971
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Aniline Compounds
- Nitriles
- Quinolines
- bosutinib
- Tretinoin
- src-Family Kinases
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Topics |
- Aniline Compounds
(pharmacology, therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology, 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, pathology)
- Nitriles
(pharmacology, therapeutic use)
- Quinolines
(pharmacology, therapeutic use)
- Signal Transduction
(drug effects)
- Tretinoin
(pharmacology)
- src-Family Kinases
(antagonists & inhibitors, metabolism)
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