The effect of CRM1 inhibition on human non-Hodgkin lymphoma cells

Abeykoon, Jithma P.; Paludo, Jonas; Nowakowski, Kevin E.; Stenson, Mary; King, Rebecca; Wellik, Linda; Wu, Xiaosheng; Witzig, Thomas E.

doi:10.1038/s41408-019-0188-6

Cited by 7 publications

(6 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…38 Previous studies have shown that KPT-330 single agent treatment leads to G 0 /G 1 cell cycle arrest and some have reported that KPT-330 single agent treatment could result in decreased expression of CRM1 and Rad51, leading to a DNA damage phenotype. 8,[39][40][41][42][43][44][45][46][47][48][49][50] Further, in MCL cell lines, KPT-330 has been shown to induce G 0 /G 1 phase arrest and could overcome inherit ibrutinib resistance through NFkB inhibition. 51 In our experimental model, we did not find a significant decrease in CRM1 or Rad51 expression with single agent KPT-330 treatment ( Figure 4G and supplemental Figure 1B).…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we demonstrated that KPT-330 treatment re-localizes i-kappa-beta (IKβ) to the nucleolus in non-Hodgkin lymphoma (NHL) cells. 8 Pairing this finding with the ability of salicylates to localize RelA (p65) to the nucleolus in cancer cells 13 , we questioned whether salicylates could potentiate the anti-tumor effect of CRM1 inhibitors. To that end, we assessed the anti-tumor activity of various CRM1 inhibitors -leptomycin B (LMB), KPT-185, and KPT-330; in combination with well-established salicylate compounds -acetyl salicylate (AS), sodium salicylate (NaS), and CS.…”

Section: Increased Potency Of Crm1 Inhibitors When Combined With Salimentioning

confidence: 99%

“…2 In tumor cells, CRM1 expression is often upregulated to facilitate the increased demand for nuclear export of proteins including tumor suppressor proteins, leading to enhanced proliferation and survival. [2][3][4][5][6][7][8] Accordingly, CRM1 has gained attention as a novel target in anticancer therapeutics.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Salicylates enhance CRM1 inhibitor antitumor activity by induction of S-phase arrest and impairment of DNA-damage repair

Abeykoon¹,

Wu²,

Nowakowski³

et al. 2021

Blood

Self Cite

View full text Add to dashboard Cite

Chromosome region maintenance protein1 (CRM1) mediates protein export from the nucleus and is a new target for anti-cancer therapeutics. Broader application of KPT-330 (selinexor), a first in class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the anti-tumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid organ cancers ex vivo and in vivo. The K+CS combination was not toxic to non-malignant cells as compared to malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared to KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51 and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of PARP inhibitors further potentiates the K+CS anti-tumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Increased Potency Of Crm1 Inhibitors When Combined With Salimentioning

confidence: 99%

See 1 more Smart Citation

Salicylates enhance CRM1 inhibitor antitumor activity by induction of S-phase arrest and impairment of DNA-damage repair

Abeykoon¹,

Wu²,

Nowakowski³

et al. 2021

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…Consistent with these biological effects, selinexor reduces the growth and viability of many solid tumors, non-Hodgkin lymphoma, myeloma and leukemia cells in vitro and in vivo [ 16 , 30 , 46 , 47 ]. Notably, studies in AML and ALL have suggest selinexor also targets the leukemic stem cells, a small subpopulation of leukemia cells, which are thought drive the relapse in AML [ 48 , 49 ].…”

Section: Selective Inhibitors Of Nuclear Export (Sine)mentioning

confidence: 98%

Targeting nuclear import and export in hematological malignancies

Nachmias

Schimmer

2020

Leukemia

View full text Add to dashboard Cite

The transport of proteins across the nuclear membrane is a highly regulated process, essential for the cell function. This transport is actively mediated by members of the karyopherin family, termed importins, or exportins, depending on the direction of transport. These proteins play an active part in tumorigenesis, through aberrant localization of their cargoes, which include oncogenes, tumor-suppressor genes and mediators of key signal transduction pathways. Overexpression of importins and exportins is reported in many malignancies, with implications in cell growth and viability, differentiation, drug resistance, and tumor microenvironment. Given their broad significance across tumors and pathways, much effort is being put to develop specific inhibitors as a novel anticancer therapeutics. Already, selinexor, a specific inhibitor of exportin-1 (XPO1), is approved for clinical use. This review will focus on the role of importins and exportins in hematological malignancies. We will discuss current preclinical and clinical data on importins and exportins, and demonstrate how our growing understanding of their functions has identified new therapeutic targets.

show abstract

“…In general, CRM1-mediated substrate protein transportation is strictly controlled, but in cancer cells, abnormally high expression of CRM1 often causes abnormal regulation of nuclear-cytoplasmic translocation of proteins, promoting tumorigenesis and tumor progression. CRM1 is widely expressed in tissues and cells, and its high expression is closely related to tumorigenesis and drug resistance [9,10]. In many malignant tumors, such as ovarian cancer, osteosarcoma, and pancreatic cancer, high CRM1 expression is associated with poor prognosis in patients [11].…”

mentioning

confidence: 99%

Reversible inhibitor of CRM1 sensitizes glioblastoma cells to radiation by blocking the NF-κB signaling pathway

Liu

Wang

et al. 2020

Cancer Cell Int

View full text Add to dashboard Cite

Background: Activation of nuclear factor-kappa B (NF-κΒ) through DNA damage is one of the causes of tumor cell resistance to radiotherapy. Chromosome region 1 (CRM1) regulates tumor cell proliferation, drug resistance, and radiation resistance by regulating the nuclear-cytoplasmic translocation of important tumor suppressor proteins or protooncoproteins. A large number of studies have reported that inhibition of CRM1 suppresses the activation of NF-κΒ. Thus, we hypothesize that the reversible CRM1 inhibitor S109 may induce radiosensitivity in glioblastoma (GBM) by regulating the NF-κΒ signaling pathway. Methods: This study utilized the cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), and colony formation assay to evaluate the effect of S109 combined with radiotherapy on the proliferation and survival of GBM cells. The therapeutic efficacy of S109 combined with radiotherapy was evaluated in vivo to explore the therapeutic mechanism of S109-induced GBM radiosensitization. Results: We found that S109 combined with radiotherapy significantly inhibited GBM cell proliferation and colony formation. By regulating the levels of multiple cell cycle-and apoptosis-related proteins, the combination therapy induced G1 cell cycle arrest in GBM cells. In vivo studies showed that S109 combined with radiotherapy significantly inhibited the growth of intracranial GBM and prolonged survival. Importantly, we found that S109 combined with radiotherapy promoted the nuclear accumulation of IκΒα, and inhibited phosphorylation of p65 and the transcriptional activation of NF-κΒ. Conclusion: Our findings provide a new therapeutic regimen for improving GBM radiosensitivity as well as a scientific basis for further clinical trials to evaluate this combination therapy.

show abstract

The effect of CRM1 inhibition on human non-Hodgkin lymphoma cells

Cited by 7 publications

References 12 publications

Salicylates enhance CRM1 inhibitor antitumor activity by induction of S-phase arrest and impairment of DNA-damage repair

Salicylates enhance CRM1 inhibitor antitumor activity by induction of S-phase arrest and impairment of DNA-damage repair

Targeting nuclear import and export in hematological malignancies

Reversible inhibitor of CRM1 sensitizes glioblastoma cells to radiation by blocking the NF-κB signaling pathway

Contact Info

Product

Resources

About