Combined staurosporine and retinoic acid induces differentiation in retinoic acid resistant acute promyelocytic leukemia cell lines.
All-trans retinoic acid (ATRA) resistance has been a critical problem in acute promyelocytic leukemia (APL) relapsed patients. In ATRA resistant APL cell lines NB4-R1 and NB4-R2, the combination of staurosporine and ATRA synergized to trigger differentiation accompanied by significantly enhanced protein level of CCAAT/enhancer binding protein ε (C/EBPε) and C/EBPβ as well as the phosphorylation of mitogen-activated protein (MEK) and extracellular signal-regulated kinase (ERK). Furthermore, attenuation of the MEK activation blocked not only the differentiation but also the increased protein level of C/EBPε and C/EBPβ. Taken together, we concluded that the combination of ATRA and staurosporine could overcome differentiation block via MEK/ERK signaling pathway in ATRA-resistant APL cell lines.
1] Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China [2] Department of Hematology, Peace Hospital of Changzhi Medical Colledge, Changzhi 046000, China.
Dong-zheng
DZ
Ge
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Yan
Y
Sheng
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Xun
X
Cai
D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D019311:Staurosporine / Q000031:analogs & derivatives*; D014212:Tretinoin / Q000494:pharmacology*
D022762:CCAAT-Enhancer-Binding Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D019311:Staurosporine