Inhibition of CK2{alpha} and PI3K/Akt synergistically induces apoptosis of CD34+CD38- leukaemia cells while sparing haematopoietic stem cells.

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Authors: JUNE-WON CHEONG ; YOO HONG MIN ; JU IN EOM ; SOO JEONG KIM ; HOI KYUNG JEUNG ; JIN SEOK KIM

MeSH: ADP-ribosyl Cyclase 1/metabolism ; Antigens, CD34/metabolism ; Apigenin/pharmacology ; Apoptosis/drug effects* ; Blotting, Western ; Casein Kinase II/antagonists & inhibitors* ; Casein Kinase II/metabolism ; Cells, Cultured ; Chromones/pharmacology ; Cytosol/metabolism ; Drug Synergism ; Elafin/antagonists & inhibitors* ; Elafin/metabolism ; Enzyme Inhibitors/pharmacology ; Hematopoietic Stem Cells/cytology* ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Humans ; Leukemia/drug therapy ; Leukemia/metabolism ; Leukemia/pathology* ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Mitochondria/metabolism ; Morpholines/pharmacology ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology* ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors* ; Proto-Oncogene Proteins c-akt/metabolism

Abstract: BACKGROUND/AIM: The CD34(+)CD38(-) leukaemia cell population contains leukaemia stem cells (LSCs) responsible for treatment failure in acute myeloid leukaemia (AML) and, thus, novel therapies are required to eradicate LSCs without harming healthy haematopoietic stem cells (HSC).

MATERIALS AND METHODS: The present study evaluated the effects of co-treatment with LY294002 (a PI3K/Akt inhibitor) and apigenin (a CK2 inhibitor) (LY/Api) at subtoxic concentrations on leukaemia cell lines and primary AML cells.

RESULTS: LY/Api synergistically induced apoptosis in leukaemia cells, especially CD34(+)CD38(-) leukaemia cells. However, these effects were negligible in HSCs. LY/Api-induced apoptosis was accompanied by activation of caspase cascades and disruption of mitochondrial membrane potential. Caspase inhibitor or Akt overexpression abrogated this synergistic induction in apoptosis by LY/Api. LY/Api also led to remarkable down-regulation of anti-apoptotic proteins including Bcl-xL and NF-κB in CD34(+)CD38(-) leukaemia cells, but not in healthy hematopoietic stem cells.

CONCLUSION: Inhibition of both CK2 and PI3K/Akt pathways may be a promising LSCs-targeted therapeutic strategy for AML.

Appears in Collections:: 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers

Yonsei Authors: Kim, Soo Jeong(김수정) https://orcid.org/0000-0001-8859-3573
Kim, Jin Seok(김진석) https://orcid.org/0000-0001-8986-8436
Min, Yoo Hong(민유홍) https://orcid.org/0000-0001-8542-9583
Eom, Ju In(엄주인)
Cheong, June-Won(정준원) https://orcid.org/0000-0002-1744-0921

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YUHSpace: Inhibition of CK2{alpha} and PI3K/Akt synergistically induces apoptosis of CD34+CD38- leukaemia cells while sparing haematopoietic stem cells.