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, Kensuke Kojima

研究成果: Contribution to journalArticle査読

11 被引用数 (Scopus)

抄録

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 patientderived 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.

本文言語英語
ページ(範囲)28547-28560
ページ数14
ジャーナルOncotarget
9
47
DOI
出版ステータス出版済み - 6 19 2018
外部発表はい

All Science Journal Classification (ASJC) codes

  • 腫瘍学

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