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Promising efficacy of novel BTK inhibitor AC0010 in mantle cell lymphoma

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

We researched into the effect and mechanism of AC0010, a novel BTK inhibitor, in MCL, and compared its efficacy and safety with Ibrutinib to develop a preclinical study for the future therapy of MCL.

Methods

MTS assay was used to detect the growth inhibition caused by AC0010 and Ibrutinib, respectively, in MCL cell lines (Jeko-1 and JVM-2), primary MCL cells, and normal peripheral lymphocytes. Apoptosis of Jeko-1 and JVM-2 after exposure into AC0010 and Ibrutinib was conducted by flow cytometry; the expression of apoptosis-related proteins was checked by Western blot. q-PCR and Western blot were applied to examine the expression of BTK and p-BTK at mRNA and protein level as well as the BTK-ralated signaling pathways. MCL xenograft was developed to testify the efficacy and safety of AC0010 in vivo.

Results

In contrast with Ibrutinib, AC0010 proved to be more toxic to MCL cells in vitro (p < 0.01) with no augment in cytotoxicity to normal peripheral lymphocytes, and it can induce obvious apoptosis in MCL cell lines (p < 0.01) through caspase family and Bcl-2 family. AC0010 at 300 mg/kg can prolong the survival rate in MCL xenograft (p < 0.01). The phosphorylation of BTK is inhibited by AC0010 following simultaneously inhibition of BCR-BTK and PI3K/AKT signaling pathway in MCL cells.

Conclusion

AC0010 is a novel BTK inhibitor of great efficacy and safety in MCL.

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Abbreviations

MCL:

Mantle cell lymphoma

NHL:

Non-Hodgkin’s lymphoma

BCR:

B-cell receptor

BTK:

Bruton tyrosine kinase

CLL:

Chronic lymphocytic leukemia

EGFR:

Epidermal growth factor receptor

SOPs:

Standard operating procedures

SCID:

Mice severe combined immunodeficient

IC50 :

Half-maximal inhibitory concentrations

FBS:

Fetal bovine serum

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Acknowledgements

We would like to thank ACEA Pharmaceutical Research for providing us with AC0010.

Funding

This work was supported by the National Natural Science Foundation of China (Grant number: 81370643, 81470305, and 81670124) and Zhejiang Provincial Key Innovation Team (Grant number: 2011R50015).

Author information

Author notes

  1. Xiao Yan and Yile Zhou have equally contributed to the work and share first authorship.

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China

    Xiao Yan, Yile Zhou, Shujuan Huang, Xia Li, Jiansong Huang, Jinghan Wang, Zhixin Ma, Jingrui Jin, Jiajia Pan, Chenying Li, Fenglin Li & Jie Jin

  2. Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China

    Xiao Yan, Yile Zhou, Shujuan Huang, Xia Li, Mengxia Yu, Jiansong Huang, Jinghan Wang, Zhixin Ma, Jingrui Jin, Jiajia Pan, Chenying Li, Fenglin Li & Jie Jin

  3. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China

    Xiao Yan, Yile Zhou, Shujuan Huang, Xia Li, Jiansong Huang, Jinghan Wang, Zhixin Ma, Jingrui Jin, Jiajia Pan, Chenying Li, Fenglin Li & Jie Jin

  4. Department of Hematology, Hangzhou First People’s Hospital, Hangzhou, Zhejiang, China

    Mengxia Yu

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  1. Xiao Yan
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  2. Yile Zhou
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Corresponding author

Correspondence to Jie Jin.

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Conflict of interest

The authors declare no conflict of interest to report.

Ethical approval

Animal experiment was performed according to the guidelines and SOPs approved by the Department of Science and Technology of Zhejiang Province, China. All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee of the First Affiliated Hospital, Zhejiang University School of Medicine.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Yan, X., Zhou, Y., Huang, S. et al. Promising efficacy of novel BTK inhibitor AC0010 in mantle cell lymphoma. J Cancer Res Clin Oncol 144, 697–706 (2018). https://doi.org/10.1007/s00432-017-2570-8

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  • DOI: https://doi.org/10.1007/s00432-017-2570-8

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