title: Effector mechanisms of sunitinib-induced G1 cell cycle arrest, differentiation, and apoptosis in human acute myeloid leukaemia HL60 and KG-1 cells.
abstract: Acute myeloid leukaemia (AML) is a heterogeneous disease with dismal outcome. Sunitinib is an orally active inhibitor of multiple tyrosine kinase receptors approved for renal cell carcinoma and gastrointestinal stromal tumour that has also been studied for AML in several clinical trials. However, the precise mechanism of sunitinib action against AML remains unclear and requires further investigation. For this purpose, this study was conducted using human AML cell lines (HL60 and KG-1) and AML patients' mononucleated cells. Sunitinib induced G1 phase arrest associated with decreased cyclin D1, cyclin D3, and cyclin-dependent kinase (Cdk)2 and increased p27(Kip1), pRb1, and p130/Rb2 expression and phosphorylated activation of protein kinase C alpha and beta (PKCα/β). Selective PKCα/β inhibitor treatment abolished sunitinib-elicited AML differentiation, suggesting that PKCα/β may underlie sunitinib-induced monocytic differentiation. Furthermore, sunitinib increased pro-apoptotic molecule expression (Bax, Bak, PUMA, Fas, FasL, DR4, and DR5) and decreased anti-apoptotic molecule expression (Bcl-2 and Mcl-1), resulting in caspase-2, caspase-3, caspase-8, and caspase-9 activation and both death receptor and mitochondria-dependent apoptosis. Taken together, these findings provide evidence that sunitinib targets AML cells through both differentiation and apoptosis pathways. More clinical studies are urgently needed to demonstrate its optimal clinical applications in AML.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China.
authors.forename: Chieh-Lin Jerry
authors.initials: CL
authors.lastname: Teng
authors.forename: Chang-Tze Ricky
authors.initials: CT
authors.lastname: Yu
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Hwang
authors.forename: Jia-Rong
authors.initials: JR
authors.lastname: Tsai
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Liu
authors.forename: Guang-Yuh
authors.initials: GY
authors.lastname: Hwang
authors.forename: Shih-Lan
authors.initials: SL
authors.lastname: Hsu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use*; D000077210:Sunitinib; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib