Promising efficacy of novel BTK inhibitor AC0010 in mantle cell lymphoma

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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