Promising efficacy of novel BTK inhibitor AC0010 in mantle cell lymphoma

  • J Cancer Res Clin Oncol. 2018 Apr;144(4):697-706. doi: 10.1007/s00432-017-2570-8.
Xiao Yan  1  2  3 ,  Yile Zhou  1  2  3 ,  Shujuan Huang  1  2  3 ,  Xia Li  1  2  3 ,  Mengxia Yu  2  4 ,  Jiansong Huang  1  2  3 ,  Jinghan Wang  1  2  3 ,  Zhixin Ma  1  2  3 ,  Jingrui Jin  1  2  3 ,  Jiajia Pan  1  2  3 ,  Chenying Li  1  2  3 ,  Fenglin Li  1  2  3 ,  Jie Jin  5  6  7
Affiliations
  • 1. Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China.
  • 2. Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China.
  • 3. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
  • 4. Department of Hematology, Hangzhou First People's Hospital, Hangzhou, Zhejiang, China.
  • 5. Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China. [email protected].
  • 6. Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China. [email protected].
  • 7. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
PMID: 29392403 DOI: 10.1007/s00432-017-2570-8
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.

Keywords
AC0010; BTK inhibitor; Ibrutinib; MCL.
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