Selective inhibitors of nuclear export for the treatment of non-Hodgkin's lymphomas

Abstract

The nuclear export protein chromosome maintenance region 1, found to be elevated in non-Hodgkin's lymphomas, controls localization of critical tumor suppressor proteins. Nuclear localization of tumor suppressor proteins is necessary for their cell surveillance function. However, their nuclear exclusion by chromosome maintenance region 1 renders them ineffective making this nuclear transporter an attractive therapeutic target. We have identified selective inhibitors of nuclear export that lock tumor suppressor proteins in the cell nucleus leading to apoptosis of lymphoid but not normal cells. Our inhibitors induce tumor suppressor protein nuclear retentiondependent growth inhibition and apoptosis in a panel of non-Hodgkin's lymphoma cell lines. Western blot of nuclear protein fraction and confocal microscopy analysis demonstrated retention of major tumor suppressor proteins in the cell nucleus. Co-immunoprecipitation studies showed disruption of the tumor suppressor proteinchromosome maintenance region 1 interaction. Small inhibitor RNA knockdown of two major tumor suppressor proteins, p53 in wild-type protein-53 and protein 73 in mutant-protein-53, abrogated inhibitor activity. Oral administration of related inhibitor at 75 and 150 mg/kg resulted in 65 and 70% tumor reduction, respectively and subcutaneous injections of inhibitor (25 and 75 mg/kg) resulted in 70 and 74% suppression of non-Hodgkin's lymphoma tumor growth with no toxicity; residual tumors showed activation of the protein 73 pathway. Our study verifies chromosome maintenance region 1 as a therapeutic target in non-Hodgkin's lymphoma, indicating that this nuclear export protein warrants further clinical investigations.

Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma

“…10 Selinexor is tumoricidal in preclinical models across a broad spectrum of cancer types. [14][15][16][17][18] Verdinexor, an analog of selinexor, produced a 34% objective response (OR) rate in clinical trials in spontaneous canine lymphoma. [14][15][16][17][18][19] On the basis of these findings, we initiated an international, multicenter phase 1 clinical trial to assess the effects of selinexor in patients with advanced hematologic malignancies.…”

Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias

“…In fact, KPT-330 treatment of BCR-ABL1 1 myeloid precursors induced nuclear accumulation of the p53 tumor suppressor and its transcriptional target p21, the reactive oxygen species detoxifier and antagonist of cell cycle progression FoxO3a, and the negative nuclear factor kB regulator IKBa, in agreement with the effect of SINEs on these XPO1 targets in other myeloid and lymphoid malignancies. [22][23][24][25][26]28,32,52 Likewise, it seems that KPT-330 negatively also regulates the activity of BCR-ABL1 downstream effectors such as STAT5, Akt, and MAPK independently from downregulation of BCR-ABL1 kinase activity. Note that binding and kinase assays exclude a direct effect of KPT-330 on these molecules and other factors regulating cell proliferation and survival (not shown).…”

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

“…SINEs specifically bind Cys528, located in NES-binding groove of CRM1, to promote nuclear retention of p53, p21, p27, Rb, and BRCA 1 [68] . The effects on hematologic malignancies of KPT-330, the most effective SINE, have been reported [69][70][71][72][73] . KPT-330 had anti-proliferative effects and induced apoptosis of an HCC cell line [74] in which p53-upregulated-modulator of apoptosis was markedly up-regulated; and this was shown to be one of the similar mechanisms by which sorafenib exerts anti-HCC effects [75] .…”