Skip to Content
MilliporeSigma
  • The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents.

The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents.

Blood (2013-07-31)
Cedric Dos Santos, Tinisha McDonald, Yin Wei Ho, Hongjun Liu, Allen Lin, Stephen J Forman, Ya-Huei Kuo, Ravi Bhatia
ABSTRACT

The SRC family kinases (SFKs) and the receptor tyrosine kinase c-Kit are activated in human acute myeloid leukemia (AML) cells. We show here that the SFKs LYN, HCK, or FGR are overexpressed and activated in AML progenitor cells. Treatment with the SFK and c-KIT inhibitor dasatinib selectively inhibits human AML stem/progenitor cell growth in vitro. Importantly, dasatinib markedly increases the elimination of AML stem cells capable of engrafting immunodeficient mice by chemotherapeutic agents. In vivo dasatinib treatment enhances chemotherapy-induced targeting of primary murine AML stem cells capable of regenerating leukemia in secondary recipients. Our studies suggest that enhanced targeting of AML cells by the combination of dasatinib with daunorubicin may be related to inhibition of AKT-mediated human mouse double minute 2 homolog phosphorylation, resulting in enhanced p53 activity in AML cells. Combined treatment using dasatinib and chemotherapy provides a novel approach to increasing p53 activity and enhancing targeting of AML stem cells.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Daunorubicin hydrochloride, ≥90% (HPLC)
Sigma-Aldrich
Daunorubicin hydrochloride, meets USP testing specifications
Daunorubicin hydrochloride, European Pharmacopoeia (EP) Reference Standard