Novel small molecule inhibitor of Kpnβ1 induces cell cycle arrest and apoptosis in cancer cells

Ajayi-Smith, Aderonke; Watt, Pauline J. van der; Mkwanazi, Nonkululeko; Carden, Sarah; Trent, John O.; Leaner, Virna D.

doi:10.1016/j.yexcr.2021.112637

Cited by 7 publications

(5 citation statements)

References 45 publications

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“…3). Interestingly, INI-43 and INI-60 (INI for inhibitor of nuclear import) alter the localization of p65 and NFAT transcription factors, and are highly effective in solid tumors [48,49]. Importantly, these drugs display a minimum effect on the proliferation of noncancer cells [50].…”

Section: Discussionmentioning

confidence: 99%

Exportin 1‐mediated nuclear/cytoplasmic trafficking controls drug sensitivity of classical Hodgkin's lymphoma

et al. 2023

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Exportin 1 (XPO1) is the main nuclear export receptor that controls the subcellular trafficking and the functions of major regulatory proteins. XPO1 is overexpressed in various cancers and small inhibitors of nuclear export (SINEs) have been developed to inhibit XPO1. In primary mediastinal B‐cell lymphoma (PMBL) and classical Hodgkin's lymphoma (cHL), the XPO1 gene may be mutated on one nucleotide and encodes the mutant XPO1E571K. To understand the impact of mutation on protein function, we studied the response of PMBL and cHL cells to selinexor, a SINE, and ibrutinib, an inhibitor of Bruton tyrosine kinase. XPO1 mutation renders lymphoma cells more sensitive to selinexor due to a faster degradation of mutant XPO1 compared to the wild‐type. We further showed that a mistrafficking of p65 (RELA) and p52 (NFκB2) transcription factors between the nuclear and cytoplasmic compartments accounts for the response toward ibrutinib. XPO1 mutation may be envisaged as a biomarker of the response of PMBL and cHL cells and other B‐cell hemopathies to SINEs and drugs that target even indirectly the NFκB signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Exportin 1‐mediated nuclear/cytoplasmic trafficking controls drug sensitivity of classical Hodgkin's lymphoma

et al. 2023

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“…Cell cycle arrest and subsequent induction of apoptosis may be a promising therapeutic strategy in various cancers [ 57 , 58 , 59 ]. On the other hand, temporary cell cycle arrest, named dormancy or quiescence, is associated with drug resistance, tumor progression and metastatic potential [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

The Evidence That 25(OH)D3 and VK2 MK-7 Vitamins Influence the Proliferative Potential and Gene Expression Profiles of Multiple Myeloma Cells and the Development of Resistance to Bortezomib

2022

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Multiple myeloma (MM) remains an incurable hematological malignancy. Bortezomib (BTZ) is a proteasome inhibitor widely used in MM therapy whose potent activity is often hampered by the development of resistance. The immune system is vital in the pathophysiology of BTZ resistance. Vitamins D (VD) and K (VK) modulate the immune system; therefore, they are potentially beneficial in MM. The aim of the study was to evaluate the effect of BTZ therapy and VD and VK supplementation on the proliferation potential and gene expression profiles of MM cells in terms of the development of BTZ resistance. The U266 MM cell line was incubated three times with BTZ, VD and VK at different timepoints. Then, proliferation assays, RNA sequencing and bioinformatics analysis were performed. We showed BTZ resistance to be mediated by processes related to ATP metabolism and oxidative phosphorylation. The upregulation of genes from the SNORDs family suggests the involvement of epigenetic mechanisms. Supplementation with VD and VK reduced the proliferation of MM cells in both the non-BTZ-resistant and BTZ-resistant phenotypes. VD and VK, by restoring proper metabolism, may have overcome resistance to BTZ in vitro. This observation forms the basis for further clinical trials evaluating VD and VK as potential adjuvant therapies for MM patients.

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“…3) that is particularly relevant for studying drug response. Interestingly, INI-43 and INI-60 (INI for inhibitor of nuclear import) alter the localization of p65 and NFAT transcription factors, and are highly effective in solid tumors [47,48]. Importantly, these drugs display a minimum effect on the proliferation of non-cancer cells [49].…”

Section: Discussionmentioning

confidence: 99%

Exportin 1-mediated nuclear/cytoplasmic trafficking controls drug sensitivity of classical Hodgkin lymphoma

Caillot

Miloudi

Taly

et al. 2022

Preprint

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Exportin 1 (XPO1) is the main nuclear export receptor that controls the subcellular trafficking and the functions of major regulatory proteins. XPO1 is overexpressed in various cancers and small inhibitors of nuclear export (SINEs) have been developed to inhibit XPO1. In primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL), the XPO1 gene may be mutated on one nucleotide and encodes the mutant XPO1E571K. To understand the impact of mutation on protein function, we studied the response of PMBL and cHL cells to selinexor, a SINE, and ibrutinib, an inhibitor of Bruton tyrosine kinase. XPO1 mutation renders lymphoma cells more sensitive to selinexor due to a faster degradation of mutant XPO1 compared to the wild-type. We further showed that a mistrafficking of p65 (RELA) and p52 (NFκB2) transcription factors between the nuclear and cytoplasmic compartments accounts for the response towards ibrutinib. XPO1 mutation may be envisaged as a biomarker of the response of PMBL and cHL cells and other B-cell hemopathies, to SINEs and drugs that target even indirectly the NFκB signaling pathway.

show abstract

Novel small molecule inhibitor of Kpnβ1 induces cell cycle arrest and apoptosis in cancer cells

Cited by 7 publications

References 45 publications

Exportin 1‐mediated nuclear/cytoplasmic trafficking controls drug sensitivity of classical Hodgkin's lymphoma

Exportin 1‐mediated nuclear/cytoplasmic trafficking controls drug sensitivity of classical Hodgkin's lymphoma

The Evidence That 25(OH)D3 and VK2 MK-7 Vitamins Influence the Proliferative Potential and Gene Expression Profiles of Multiple Myeloma Cells and the Development of Resistance to Bortezomib

Exportin 1-mediated nuclear/cytoplasmic trafficking controls drug sensitivity of classical Hodgkin lymphoma

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