1. Academic Validation
  2. Vibsanin A sensitizes human acute myeloid leukemia cells to tyrosine kinase inhibitor-induced myeloid differentiation via activation of PKC and upregulation of Lyn

Vibsanin A sensitizes human acute myeloid leukemia cells to tyrosine kinase inhibitor-induced myeloid differentiation via activation of PKC and upregulation of Lyn

  • Biochem Biophys Res Commun. 2018 Jul 7;502(1):110-115. doi: 10.1016/j.bbrc.2018.05.129.
Xing Shen 1 Shuang Xing 2 Lu Zhang 3 Fangmin Wang 4 Hongling Ou 5 Yajun Shan 2 He Xiao 6 Guolin Xiong 2 Xinru Wang 5 Qinshi Zhao 7 Yuwen Cong 8 Zuyin Yu 9
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China. Electronic address: shen_xingjyk@163.com.
  • 2 Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
  • 3 Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China; Department of Clinical Laboratory, The General Hospital of PLA Rocket Force, Beijing, China.
  • 4 Department of Graduates, Anhui Medical University, Hefei, China.
  • 5 Department of Clinical Laboratory, The General Hospital of PLA Rocket Force, Beijing, China.
  • 6 Department of Molecular Immunology, Institute of Pharmacology and Toxicology, Beijing, China.
  • 7 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
  • 8 Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China. Electronic address: congyw@nic.bmi.ac.cn.
  • 9 Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China; Department of Graduates, Anhui Medical University, Hefei, China. Electronic address: yuzy79@163.com.
Abstract

Differentiation therapies have been proposed to overcome the impaired cell differentiation in acute myeloid leukemia (AML). However, thus far the all-trans retinoic acid-based differentiation therapy has been the only successful modality in treating acute promyelocytic leukemia. Here, we showed that vibsanin A, a novel protein kinase C (PKC) activator, sensitized AML cells to tyrosine kinase inhibitor (TKI)-induced differentiation. Vibsanin A augmented the ability of TKIs to induce growth inhibition and G1 cell cycle arrest of AML cells. Mechanistically, PKC activation was involved in the differentiation-inducing effects of combining vibsanin A with TKIs. Moreover, we found that vibsanin A enhanced TKI-induced Lyn expression and suppression of Lyn interfered with AML cell differentiation, indicating an essential role for Lyn expression in the combination-induced differentiation. Finally, combining vibsanin A and TKIs enhanced the activation of the Raf/MEK/ERK cascade. Together, this is the first study to evaluate the synergy of vibsanin A and TKIs in AML cell differentiation. Our study lays the foundation in assessing new opportunities for the combination of vibsanin A and TKIs as a promising approach for future differentiation therapy.

Keywords

Differentiation; Lyn; Protein kinase C; Tyrosine kinase inhibitor; Vibsanin A.

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