title: Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma.
abstract: 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.
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kejie
authors.initials: K
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Archito T
authors.initials: AT
authors.lastname: Tamayo
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.forename: John
authors.initials: J
authors.lastname: Lee
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhishuo
authors.initials: Z
authors.lastname: Ou
authors.forename: Changping
authors.initials: C
authors.lastname: Li
authors.forename: Luhong
authors.initials: L
authors.lastname: Sun
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ford
authors.forename: Lan V
authors.initials: LV
authors.lastname: Pham
mesh_terms: D000179:Acrylates / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D000097606:Exportin 1 Protein
chemical_list: D000179:Acrylates; D028884:Karyopherins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein; C576639:KPT-185