Oncotarget

Research Papers:

Targeting of BMI-1 expression by the novel small molecule PTC596 in mantle cell lymphoma

Aya Maeda, Yuki Nishida, Marla Weetall, Liangxian Cao, Arthur Branstrom, Jo Ishizawa, Takenobu Nii, Wendy D. Schober, Yoshiaki Abe, Kosei Matsue, Mariko Yoshimura, Shinya Kimura and Kensuke Kojima _

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Oncotarget. 2018; 9:28547-28560. https://doi.org/10.18632/oncotarget.25558

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Abstract

Aya Maeda1, Yuki Nishida1, Marla Weetall2, Liangxian Cao2, Arthur Branstrom2, Jo Ishizawa3, Takenobu Nii3, Wendy D. Schober3, Yoshiaki Abe4, Kosei Matsue4, Mariko Yoshimura1, Shinya Kimura1 and Kensuke Kojima1

1Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan

2PTC Therapeutics, South Plainfield, NJ, USA

3Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

4Division of Hematology/Oncology, Department of Medicine, Kameda Medical Center, Kamogawa, Japan

Correspondence to:

Kensuke Kojima, email: kkojima@cc.saga-u.ac.jp

Keywords: BMI-1; mantle cell lymphoma

Received: November 30, 2017    Accepted: May 21, 2018    Published: June 19, 2018

ABSTRACT

Despite the development of the novel Bruton tyrosine kinase inhibitor ibrutinib, mantle cell lymphoma (MCL) remains an incurable B-cell non-Hodgkin lymphoma. BMI-1 is required for the self-renewal and maintenance of MCL-initiating stem cells. Upregulation of BMI-1 has been reported in MCL patients, especially in those with refractory/relapsed disease. We studied the effects of a novel small-molecule selective inhibitor of BMI1 expression, PTC596, in MCL cells. Eight MCL cell lines and patient-derived samples were exposed to PTC596. PTC596 induced mitochondrial apoptosis, as evidenced by loss of mitochondrial membrane potential, caspase-3 cleavage, BAX activation, and phosphatidylserine externalization. There was a positive correlation between baseline BMI-1 protein levels and PTC596-induced apoptosis. p53 status did not affect sensitivity to PTC596. PTC596 effectively decreased BMI-1-expressing and tumor-initiating side population MCL cells (IC50: 138 nM) compared with ibrutinib, which modestly decreased side population cells. Interestingly, PTC596, reported to target cancer stem cells, decreased MCL-1 expression levels and antagonized ibrutinib-induced increase in MCL-1 expression, leading to synergistic apoptosis induction in MCL cells. There are currently no drugs that specifically target cancer stem cell fractions, and a reduction in BMI-1 protein by PTC596 may offer a novel therapeutic strategy for MCL.


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