Selective inhibitors of nuclear export (SINE) in hematological malignancies

Das, Arundhati; Wei, Guoqing; Parikh, Kaushal; Liu, Delong

doi:10.1186/s40164-015-0002-5

Cited by 56 publications

(47 citation statements)

References 33 publications

(50 reference statements)

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“…To test this hypothesis, in preliminary experiments we tested the nuclear export inhibitor KPT330 on ALCL cells. KPT330 is currently in clinical trial for the treatment of acute leukemia 8, 52 . Treatment with KPT330 resulted in a marked apoptosis of ALCL cells (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency

et al. 2015

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Most of Anaplastic Large Cell Lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK. NPM-ALK deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive due to heterodimerization with NPM1. Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or re-localization of NPM-ALK to the cytoplasm by NPM genetic knock-out or knock-down caused ERK1/2 increased phosphorylation and cell death through the engagement of an ATM/Chk2 and γH2AX mediated DNA damage response. Remarkably, human NPM-ALK amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A “drug holiday” where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by NPM-ALK amplification.

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Section: Discussionmentioning

confidence: 99%

Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency

et al. 2015

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“…Overexpression of CRM1 is observed in solid and hematologic malignancies (Turner and Sullivan, 2008; Parikh et al, 2014; Das et al, 2015). Overexpression of CRM1 results in mislocalization of regulatory factors away from their original site of action in the nucleus and disrupts DNA topology, tumor suppression, cell cycle, and apoptosis (Turner et al, 2012a).…”

Section: Crm1 In Cancermentioning

confidence: 99%

“…Chromosome Region Maintenance1 (CRM1) is therefore a promising cancer drug target, and the use of small molecule inhibitors of CRM1 for a variety of cancers has been reviewed in detail (Turner et al, 2012a, 2014; Gravina et al, 2014; Parikh et al, 2014; Senapedis et al, 2014; Tan et al, 2014; Das et al, 2015) and will not be discussed further.…”

Section: Crm1 In Cancermentioning

confidence: 99%

“…Two KPT SINE inhibitors (KPT 330 or Selinexor and KPT 335 or Verdinexor) are now in Phase 1/2 clinical trial for solid and hematological cancers (www.clinicaltrails.gov). SINE-mediated CRM1 inhibition enables nuclear retention of tumor suppressor proteins and anti-apoptotic signals (IκB, Survivin, p53, NPMc mutant, p27, and FOXO) and lead to cell cycle arrest and apoptosis in cancerous cells (Parikh et al, 2014; Das et al, 2015). …”

Section: Leptomycin B and Synthetic Inhibitorsmentioning

confidence: 99%

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CRM1 Inhibitors for Antiviral Therapy

Mathew

Ghildyal

2017

Front. Microbiol.

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Infectious diseases are a major global concern and despite major advancements in medical research, still cause significant morbidity and mortality. Progress in antiviral therapy is particularly hindered by appearance of mutants capable of overcoming the effects of drugs targeting viral components. Alternatively, development of drugs targeting host proteins essential for completion of viral lifecycle holds potential as a viable strategy for antiviral therapy. Nucleocytoplasmic trafficking pathways in particular are involved in several pathological conditions including cancer and viral infections, where hijacking or alteration of function of key transporter proteins, such as Chromosome Region Maintenance1 (CRM1) is observed. Overexpression of CRM1-mediated nuclear export is evident in several solid and hematological malignancies. Interestingly, CRM1-mediated nuclear export of viral components is crucial in various stages of the viral lifecycle and assembly. This review summarizes the role of CRM1 in cancer and selected viruses. Leptomycin B (LMB) is the prototypical inhibitor of CRM1 potent against various cancer cell lines overexpressing CRM1 and in limiting viral infections at nanomolar concentrations in vitro. However, the irreversible shutdown of nuclear export results in high cytotoxicity and limited efficacy in vivo. This has prompted search for synthetic and natural CRM1 inhibitors that can potentially be developed as broadly active antivirals, some of which are summarized in this review.

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“…In the patient presented in our report, the regimen containing liposomal doxorubicin was a reasonable choice in attempt to control an advanced, high-risk disease in an elderly patient with deteriorating performance status and decreased cardiac function. However, all of the above therapies carry a burden of significant toxicities and there is an increasing need for novel targeted agents for the treatment of the population of elderly and frail patients (28)(29)(30)(31)(32)(33)(34).…”

Section: Case Presentationmentioning

confidence: 99%

A rare case of the upper extremity diffuse large B-cell lymphoma mimicking soft tissue sarcoma in an elderly patient

Mamorska-Dyga

Ronny

Puccio

et al. 2016

Stem Cell Investig.

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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, with about 30% of new cases presenting with extranodal disease. Lesions originating from soft tissues of the upper extremities are extremely rare and may mimic other malignancies like sarcoma. We present a case of an elderly patient with right upper extremity (RUE) mass which was proven to be DLBCL instead of sarcoma. We emphasize the increasing need for investigating new therapeutic options for patients of extreme age and/or with underlying heart disease.

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Selective inhibitors of nuclear export (SINE) in hematological malignancies

Cited by 56 publications

References 33 publications

Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency

Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency

CRM1 Inhibitors for Antiviral Therapy

A rare case of the upper extremity diffuse large B-cell lymphoma mimicking soft tissue sarcoma in an elderly patient

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