TY - JOUR
T1 - Targeting of BMI-1 expression by the novel small molecule PTC596 in mantle cell lymphoma
AU - Maeda, Aya
AU - Nishida, Yuki
AU - Weetall, Marla
AU - Cao, Liangxian
AU - Branstrom, Arthur
AU - Ishizawa, Jo
AU - Nii, Takenobu
AU - Schober, Wendy D.
AU - Abe, Yoshiaki
AU - Matsue, Kosei
AU - Yoshimura, Mariko
AU - Kimura, Shinya
AU - Kojima, Kensuke
N1 - Funding Information:
This study was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan (17K09928), the Yasuda Medical Foundation, the Foundation for Promotion of Cancer Research in Japan and the Project Mirai Cancer Research Grants (all to Kensuke Kojima).
Publisher Copyright:
©Maeda et al.
PY - 2018/6/19
Y1 - 2018/6/19
N2 - 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.
AB - 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.
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U2 - 10.18632/oncotarget.25558
DO - 10.18632/oncotarget.25558
M3 - Article
C2 - 29983879
AN - SCOPUS:85048826006
SN - 1949-2553
VL - 9
SP - 28547
EP - 28560
JO - Oncotarget
JF - Oncotarget
IS - 47
ER -
