TY - JOUR
T1 - Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma
AU - Zhang, Kejie
AU - Wang, Michael
AU - Tamayo, Archito T.
AU - Shacham, Sharon
AU - Kauffman, Michael
AU - Lee, John
AU - Zhang, Liang
AU - Ou, Zhishuo
AU - Li, Changping
AU - Sun, Luhong
AU - Ford, Richard J.
AU - Pham, Lan V.
N1 - Funding Information:
This work was supported in part by grants from Fujian Provincial Department of Science and Technology ( 2009-CXB-57/2011J01252 ) and Bureau of Science and Technology of Xiamen , China ( 3502Z20094012 ).
PY - 2013/1
Y1 - 2013/1
N2 - Overexpression of the cellular nuclear exportin 1, more commonly called chromosomal region maintenance 1 (CRM1), has been associated with malignant progression and mortality. Therefore, activation of nuclear export can play a significant etiologic role in some forms of human neoplasia and serve as a novel target for the treatment of these cancers. Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that remains incurable. The objective of this study was to investigate the functional significance of CRM1 in MCL by evaluating the therapeutic efficacy of CRM1 inhibition in MCL in vitro and in vivo. Our results showed that CRM1 is highly expressed in MCL cells and is involved in regulating growth and survival mechanisms through the critical nuclear factor-κB survival pathway, which is independent of p53 status. Inhibition of CRM1 by two novel selective inhibitors of nuclear export (SINE), KPT-185 and KPT-276, in MCL cells resulted in significant growth inhibition and apoptosis induction. KPT-185 also induced CRM1 accumulation in the nucleus, resulting in CRM1 degradation by the proteasome. Oral administration of KPT-276 significantly suppressed tumor growth in an MCL-bearing severe combined immunodeficient mouse model, without severe toxicity. Our data suggest that SINE CRM1 antagonists are a potential novel therapy for patients with MCL, particular in relapsed/refractory disease.
AB - Overexpression of the cellular nuclear exportin 1, more commonly called chromosomal region maintenance 1 (CRM1), has been associated with malignant progression and mortality. Therefore, activation of nuclear export can play a significant etiologic role in some forms of human neoplasia and serve as a novel target for the treatment of these cancers. Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that remains incurable. The objective of this study was to investigate the functional significance of CRM1 in MCL by evaluating the therapeutic efficacy of CRM1 inhibition in MCL in vitro and in vivo. Our results showed that CRM1 is highly expressed in MCL cells and is involved in regulating growth and survival mechanisms through the critical nuclear factor-κB survival pathway, which is independent of p53 status. Inhibition of CRM1 by two novel selective inhibitors of nuclear export (SINE), KPT-185 and KPT-276, in MCL cells resulted in significant growth inhibition and apoptosis induction. KPT-185 also induced CRM1 accumulation in the nucleus, resulting in CRM1 degradation by the proteasome. Oral administration of KPT-276 significantly suppressed tumor growth in an MCL-bearing severe combined immunodeficient mouse model, without severe toxicity. Our data suggest that SINE CRM1 antagonists are a potential novel therapy for patients with MCL, particular in relapsed/refractory disease.
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U2 - 10.1016/j.exphem.2012.09.002
DO - 10.1016/j.exphem.2012.09.002
M3 - Article
C2 - 22986101
AN - SCOPUS:84870887672
SN - 0301-472X
VL - 41
SP - 67-78.e4
JO - Experimental Hematology
JF - Experimental Hematology
IS - 1
ER -