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Annals of Hematology

, Volume 92, Issue 3, pp 301–313 | Cite as

Effector mechanisms of sunitinib-induced G1 cell cycle arrest, differentiation, and apoptosis in human acute myeloid leukaemia HL60 and KG-1 cells

  • Chieh-Lin Jerry Teng
  • Chang-Tze Ricky Yu
  • Wen-Li Hwang
  • Jia-Rong Tsai
  • Hsiang-Chun Liu
  • Guang-Yuh Hwang
  • Shih-Lan Hsu
Original Article

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 p27Kip1, 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.

Keywords

Sunitinib Differentiation Apoptosis PKC Bcl-2 

Notes

Acknowledgments

We thanked Pfizer pharmaceutical company for kindly providing sunitinib compound. This work was supported by the research grant from Taichung Veterans General Hospital (TCVGH-1003701B), National Science Council (NSC99-3112-B-075A-001) and Tunghai University (TCVGH-T1007802).

Author contributions

C-L Teng and S-L Hsu performed the research and wrote the paper, W-L Hwang, C-T Yu and G-Y Hwang designed research and revised the paper, and H-C Liu and J-R Tsai performed the experiments.

Conflict of interest

The authors have no conflicting financial interests.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Chieh-Lin Jerry Teng
    • 1
    • 2
    • 3
  • Chang-Tze Ricky Yu
    • 4
  • Wen-Li Hwang
    • 1
  • Jia-Rong Tsai
    • 5
  • Hsiang-Chun Liu
    • 5
  • Guang-Yuh Hwang
    • 2
  • Shih-Lan Hsu
    • 5
  1. 1.Division of Hematology/Oncology, Department of MedicineTaichung Veterans General HospitalTaichungRepublic of China
  2. 2.Department of Life ScienceTunghai UniversityTaichungRepublic of China
  3. 3.Department of MedicineChung Shan Medical UniversityTaichungRepublic of China
  4. 4.Department of Applied ChemistryNational Chi Nan UniversityTaichungRepublic of China
  5. 5.Department of Education and ResearchTaichung Veterans General HospitalTaichungRepublic of China

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