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


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.


CONCLUSIONS
Inhibition of both CK2 and PI3K/Akt pathways may be a promising LSCs-targeted therapeutic strategy for AML.
Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea.
June-Won
JW
Cheong
Yoo Hong
YH
Min
Ju In
JI
Eom
Soo Jeong
SJ
Kim
Hoi Kyung
HK
Jeung
Jin Seok
JS
Kim
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D047310:Apigenin / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004357:Drug Synergism; D053492:Elafin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018952:Antigens, CD34; D002867:Chromones; D053492:Elafin; D004791:Enzyme Inhibitors; D009025:Morpholines; C506806:PI3 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D047310:Apigenin; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt; D051997:ADP-ribosyl Cyclase 1