XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer

Ferreiro-Neira, Isabel; Torres, Nancy E.; Liesenfeld, Lukas F.; Chan, Carlos; Penson, Tristan; Landesman, Yosef; Senapedis, William; Shacham, Sharon; Hong, Theodore S.; Cusack, James C.

doi:10.1158/1078-0432.ccr-15-0978

Cited by 42 publications

(38 citation statements)

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“…Cell survival curves were obtained by GraphPad Prism 6.0 software. Compusyn software was used to determine the synergistic effect of S109 combined with IR [28].…”

Section: Clonogenic Survivalmentioning

confidence: 99%

RETRACTED ARTICLE: Reversible inhibitor of CRM1 sensitizes glioblastoma cells to radiation by blocking the NF-κB signaling pathway

Liu

Wang

et al. 2020

Cancer Cell Int

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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.

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“…Cell survival curves were obtained by GraphPad Prism 6.0 software. Compusyn software was used to determine the synergistic effect of S109 combined with IR [28].…”

Section: Clonogenic Survivalmentioning

confidence: 99%

RETRACTED ARTICLE: Reversible inhibitor of CRM1 sensitizes glioblastoma cells to radiation by blocking the NF-κB signaling pathway

Liu

Wang

et al. 2020

Cancer Cell Int

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“…After that, the cells were lysed by 200 µL of DMSO. Then the spectrophotometric absorbance of the samples was determined using a microplate reader (Bio-Rad) (Ferreiro-Neira et al, 2016).…”

Section: Cell Growth Inhibition Assaymentioning

confidence: 99%

“…Association of XPO1 overexpression with high tumor grade and advanced tumor stage (Noske et al, 2008;Shen et al, 2009) as well as with poor prognosis was noted in some tumor cancers such as gastric (Zhou et al, 2013), ovarian (Noske et al, 2008) and acute leukemia (Kojima et al, 2013), but little is known about such association between the XPO1 overexpression and clinicopathological characteristics in CRC. In colon cancer cell lines, the XPO1 increases the oncogenic activity of tumor cells through mislocalization of some proteins such as p27 and survivin (Ferreiro-Neira et al, 2016;Heong et al, 2016). On the other hand, In CRC, NF-κB over-expression was considered as biomarker associated with worse 3 and 5 years overall survival .…”

Section: Introductionmentioning

confidence: 99%

Association of XPO1 Overexpression with NF-κB and Ki67 in Colorectal Cancer

Al-Adhraei

Al‐Thobhani

Poungvarin

et al. 2019

Asian Pac J Cancer Prev

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also known as chromosome region maintenance 1 (CRM1) protein, is involved in the homeostatic of nucleocytoplasmic transport of over 200 known cargos, most of them are tumor suppressor and cell cycle regulatory proteins such as p53, pRb, FOXOs, BRCA1/2 and inhibitor of NF-κB (Kau et al., 2004; Abstract Objectives: Exportin 1(XPO1), a nuclear exporter protein, has been gaining recognition in cancer progression and treatment. This study aimed to evaluate the association between the overexpression of XPO1 with NF-κB, Ki67 and clinicopathological characteristics in colorectal cancer (CRC) tissue samples and to explore the anti-proliferative effect of KPT-330, as XPO1 inhibitor, in colorectal cancer cell line. Methods: Forty CRC tissue samples were analyzed by immunostaining for the expressions of XPO1, NF-κB and Ki67 and then the anti-proliferative effect of the KPT-330 was also evaluated in HT29 colorectal cancer cell line. Results: XPO1 overexpression was observed in 52.5% of CRC and significantly apparent with strong intensity in tumor cells compared to the normal adjacent epithelium (P<0.001).Regarding to the histopathological characteristics, the XPO1 overexpression significantly associated with advanced tumor stages (P=0.049) and has great tendency towards moderate/poorly differentiated tumors. Although the XPO1 overexpression was strongly associated with high Ki67 expression (P=0.001), only Ki67 expression showed significant association with tumor size (P=0.012). No significant association was detected between the XPO1 overexpression and NF-κB, while the NF-κB positive expression was significantly associated with lymph node metastasis and Ki67 expression at P=0.027 and P= 0.007, respectively. The in vitro experiments showed a great impact of KPT-330, as XPO1 inhibitor, to inhibit cancer growth in dose and time dependent manner and significantly diminished the colony formation (P<0.001) of HT29 cells-associated with the expression of Ki67 (P<0.001). Conclusion: XPO1 overexpression and NF-κB expression may serve as potential biomarker associated with CRC pathogenesis and proliferation, while the KPT-330 is effectively inhibited-colon cancer growth in vitro. Further studies considering the prognostication role of XPO1 overexpression in CRC are required.

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“…It has been reported that downregulation and inhibition of survivin could enhance the radiosensitivity of cancer cells. 30 , 31 …”

Section: Discussionmentioning

confidence: 99%

Inhibition of survivin enhances radiosensitivity of esophageal cancer cells by switching radiation-induced senescence to apoptosis

Liu¹,

Zhao²,

Zhang³

et al. 2018

OTT

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PurposeStrategies to increase radiosensitivity are urgently needed. Combining radiosensitizing reagents with radiotherapy could improve the outcome of cancer treatment. Some preclinical studies showed that sepantronium bromide (YM155) could sensitize cancer cells to radiation by inhibiting the survivin protein. In this study, we try to investigate the function of YM155 on radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells.Materials and methodsESCC cell lines were treated with radiation and YM155, and the radiation efficacy was evaluated by cell counting kit-8 assay and clonogenic survival assay. Cell senescence was measured by senescence-associated β-galactosidase staining. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, fluorescein isothiocyanate-labeled Annexin V/propidium iodide assay, and poly ADP-ribose polymerase cleavage were used to detect apoptosis. KYSE150 xenografts model was used to test the efficacy of radiation combined with YM155.ResultsYM155 could inhibit the upregulation of survivin induced by radiation in all ESCC cell lines, but the efficacy of radiosensitization varied in different cell lines. Radiation-induced senescence in KYSE150 and KYSE410 cells, and the combination with YM155 inhibited senescence and promoted apoptosis of ESCC cells, thereby enhancing radiosensitivity. Combination with YM155 and radiation delayed the growth of KYSE150 xenografts in nude mice by switching radiation-induced senescence to apoptosis. When p21 was inhibited in KYSE150 cells, radiation did not induce senescence, and the radiosensitization of YM155 was also attenuated. In KYSE510 and KYSE180 cells, radiation did not induce senescence, and YM155 could not enhance the radiosensitivity.ConclusionOur results suggest a new mechanism that YM155 might sensitize ESCC cells to radiation by switching radiation-induced senescence to apoptosis. The major determinant of radiosensitization by YM155 might be the induction of senescence by radiation.

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XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer

Cited by 42 publications

References 50 publications

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

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

Association of XPO1 Overexpression with NF-κB and Ki67 in Colorectal Cancer

Inhibition of survivin enhances radiosensitivity of esophageal cancer cells by switching radiation-induced senescence to apoptosis

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