[The anti-tumoral effect of PI3K inhibitor and MEK inhibitor combined with STI571 on chronic myeloid leukemia cells in a bone marrow stromal cell co-culture system].
The goal of this study was to elucidate the functional roles of PI3K/AKT and MEK/ERK signaling on the proliferation and apoptosis of STI571-sensitive and -resistant CML cell lines in a co-culture system with human marrow stromal cells (MSCs), mimicking the bone marrow microenvironment. The phosphorylation of AKT and ERK was enhanced by co-culture with MSCs in both STI571-sensitive KBM-5 and STI571-resistant KBM-5/STI cells. In KBM-5 cells, the STI571 and PI3K inhibitor LY294002 combination was effective on apoptosis induction in the MSC co-culture system. In KBM-5/STI cells, treatment with LY294002 or PD98059 alone resulted in massive apoptosis, which was enhanced by co-culture with MSCs. These results provide a rationale for multi-molecular target therapy approaches based on a combination of signal transduction inhibitors with STI571 in CML.
Jin
Linhua
L
Department of Clinical Pathology, Juntendo University School of Medicine.
Kato
Atsushi
A
Tabe
Yoko
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D001854:Bone Marrow Cells / Q000166:cytology*; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D018920:Coculture Techniques; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects*
D000970:Antineoplastic Agents; D001549:Benzamides; D002867:Chromones; D005419:Flavonoids; D000068877:Imatinib Mesylate; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one