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  • 1
    Online Resource
    Online Resource
    Inhibition of STAT3 by Niclosamide Synergizes with Erlotinib against Head and Neck Cancer
    Public Library of Science (PLoS) ; 2013
    In:  PLoS ONE Vol. 8, No. 9 ( 2013-9-3), p. e74670-
    Details
    In: PLoS ONE, Public Library of Science (PLoS), Vol. 8, No. 9 ( 2013-9-3), p. e74670-
    Type of Medium: Online Resource
    ISSN: 1932-6203
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1371/journal.pone.0074670
    DOI: 10.1371/journal.pone.0074670.g001
    DOI: 10.1371/journal.pone.0074670.g002
    DOI: 10.1371/journal.pone.0074670.g003
    DOI: 10.1371/journal.pone.0074670.g004
    DOI: 10.1371/journal.pone.0074670.g005
    DOI: 10.1371/journal.pone.0074670.g006
    DOI: 10.1371/journal.pone.0074670.g007
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2013
    detail.hit.zdb_id: 2267670-3
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  • 2
    Online Resource
    Online Resource
    Novel Small-Molecule Inhibitors of Bcl-XL to Treat Lung Cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 17 ( 2013-09-01), p. 5485-5496
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 17 ( 2013-09-01), p. 5485-5496
    Abstract: Bcl-XL is a major antiapoptotic protein in the Bcl-2 family whose overexpression is more widely observed in human lung cancer cells than that of Bcl-2, suggesting that Bcl-XL is more biologically relevant and therefore a better therapeutic target for lung cancer. Here, we screened small molecules that selectively target the BH3 domain (aa 90–98) binding pocket of Bcl-XL using the UCSF DOCK 6.1 program suite and the NCI chemical library database. We identified two new Bcl-XL inhibitors (BXI-61 and BXI-72) that exhibit selective toxicity against lung cancer cells compared with normal human bronchial epithelial cells. Fluorescence polarization assay reveals that BXI-61 and BXI-72 preferentially bind to Bcl-XL protein but not Bcl2, Bcl-w, Bfl-1/A1, or Mcl-1 in vitro with high binding affinities. Treatment of cells with BXI-72 results in disruption of Bcl-XL/Bak or Bcl-XL/Bax interaction, oligomerization of Bak, and cytochrome c release from mitochondria. Importantly, BXI-61 and BXI-72 exhibit more potent efficacy against human lung cancer than ABT-737 but less degree in platelet reduction in vivo. BXI-72 overcomes acquired radioresistance of lung cancer. On the basis of our findings, the development of BXI(s) as a new class of anticancer agents is warranted and represents a novel strategy for improving lung cancer outcome. Cancer Res; 73(17); 5485–96. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-2272
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 3
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    Abstract 2758: Development of small molecule Bax agonists for lung cancer treatment
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2758-2758
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2758-2758
    Abstract: Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently discovered that the serine(S) 184 site on Bax is a critical functional switch for controlling the proapoptotic activity of Bax. The structural pocket around the S184 residue holds great promise as an ideal target for small molecule docking. We therefore employed the S184 residue as a docking site for screening small molecule therapeutic agents using the UCSF DOCK program suite and the NCI library of small molecules. Three compounds named small molecule Bax agonists (i.e. SMBA1, SMBA2 and SMBA3) were found to induce a conformational change of Bax by blocking phosphorylation of its S184 site, facilitating Bax insertion into mitochondrial membranes and formation of Bax oligomers leading to cytochrome c release and apoptosis in human lung cancer cells. Intriguingly, SMBA1 potently suppresses lung tumor growth via apoptosis in vivo without significant normal tissue toxicity. Survival outcomes remain very poor for lung cancer patients due to resistance to standard therapeutic interventions with radiation and systemic chemotherapy. Development of novel Bax agonists as an entirely new class of anti-cancer drugs has translational value to foster novel strategies for the treatment of lung cancer and other Bax expressing malignancies. Citation Format: Meiguo Xin, Rui Li, Dongkyoo Park, Taofeek K. Owonikoko, Gabriel L. Sica, Patrick E. Corsino, Jia Zhou, Chunyong Ding, Andrew T. Magis, Suresh S. Ramalingam, Walter J. Curran, Fadlo R. Khuri, Xingming Deng. Development of small molecule Bax agonists for lung cancer treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2758. doi:10.1158/1538-7445.AM2014-2758
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-2758
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 4
    Online Resource
    Online Resource
    Abstract 3449: Development of small molecule Bcl-XL inhibitors for treatment of lung cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3449-3449
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3449-3449
    Abstract: Bcl-XL is a major anti-apoptotic protein in the Bcl-2 family whose overexpression is more widely observed in human lung cancer cells than that of Bcl-2, suggesting that Bcl-XL is more biologically relevant and therefore a better therapeutic target for lung cancer. Here, we screened small molecules that selectively target the BH3 domain (aa 90-98) binding pocket of Bcl-XL using the UCSF DOCK 6.1 program suite and the NCI chemical library database. We identified two new Bcl-XL inhibitors (BXI-61 and BXI-72) that exhibit selective toxicity against lung cancer cells compared with normal human bronchial epithelial cells. Fluorescence polarization assay reveals that BXI-61 and BXI-72 preferentially bind to Bcl-XL protein but not Bcl2 in vitro with high binding affinities. Treatment of cells with BXI-72 results in disruption of Bcl-XL/Bak interaction, oligomerization of Bak and cytochrome c release from mitochondria. These two BXI compounds potently repress lung cancer xenografts in vivo without significant normal tissue toxicity within effective doses. Importantly, BXI-72 can also overcome acquired radioresistance of lung cancer. Based on our findings, the development of BXI(s) as a new class of anticancer agents is warranted and represents a novel strategy for improving lung cancer outcome. Citation Format: Dongkyoo Park, Andrew T. Magis, Rui Li, Taofeek K. K. Owonikoko, Gabriel L. Sica, Shi-Yong Sun, Suresh S. Ramalingam, Fadlo R. Khuri, Walter J. Curran, Xingming Deng. Development of small molecule Bcl-XL inhibitors for treatment of lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3449. doi:10.1158/1538-7445.AM2013-3449
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3449
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 5
    Online Resource
    Online Resource
    Niclosamide Overcomes Acquired Resistance to Erlotinib through Suppression of STAT3 in Non–Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 10 ( 2013-10-01), p. 2200-2212
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 10 ( 2013-10-01), p. 2200-2212
    Abstract: The emergence of resistance to EGF receptor (EGFR) inhibitor therapy is a major clinical problem for patients with non–small cell lung cancer (NSCLC). The mechanisms underlying tumor resistance to inhibitors of the kinase activity of EGFR are not fully understood. Here, we found that inhibition of EGFR by erlotinib induces STAT3 phosphorylation at Tyr705 in association with increased Bcl2/Bcl-XL at both mRNA and protein levels in various human lung cancer cells. PTPMeg2 is a physiologic STAT3 phosphatase that can directly dephosphorylate STAT3 at the Tyr705 site. Intriguingly, treatment of cells with erlotinib results in downregulation of PTPMeg2 without activation of STAT3 kinases [i.e., Janus-activated kinase (JAK2) or c-Src], suggesting that erlotinib-enhanced phosphorylation of STAT3 may occur, at least in part, from suppression of PTPMeg2 expression. Because elevated levels of phosphorylated STAT3 (pSTAT3), Bcl2, and Bcl-XL were observed in erlotinib-resistant lung cancer (HCC827/ER) cells as compared with erlotinib-sensitive parental HCC827 cells, we postulate that the erlotinib-activated STAT3/Bcl2/Bcl-XL survival pathway may contribute to acquired resistance to erlotinib. Both blockage of Tyr705 phosphorylation of STAT3 by niclosamide and depletion of STAT3 by RNA interference in HCC827/ER cells reverse erlotinib resistance. Niclosamide in combination with erlotinib potently represses erlotinib-resistant lung cancer xenografts in association with increased apoptosis in tumor tissues, suggesting that niclosamide can restore sensitivity to erlotinib. These findings uncover a novel mechanism of erlotinib resistance and provide a novel approach to overcome resistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway in human lung cancer. Mol Cancer Ther; 12(10); 2200–12. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-13-0095
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2062135-8
    detail.hit.zdb_id: 2063563-1
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Disruption of STAT3 by Niclosamide Reverses Radioresistance of Human Lung Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Molecular Cancer Therapeutics Vol. 13, No. 3 ( 2014-03-01), p. 606-616
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 13, No. 3 ( 2014-03-01), p. 606-616
    Abstract: A major challenge affecting the outcomes of patients with lung cancer is the development of acquired radioresistance. However, the mechanisms underlying the development of resistance to therapy are not fully understood. Here, we discovered that ionizing radiation induces phosphorylation of Janus-associated kinase (JAK)-2 and STAT3 in association with increased levels of Bcl2/Bcl-XL in various human lung cancer cells. To uncover new mechanism(s) of radioresistance of lung cancer, we established lung cancer cell model systems with acquired radioresistance. As compared with radiosensitive parental lung cancer cells (i.e., A549, H358, and H157), the JAK2/STAT3/Bcl2/Bcl-XL survival pathway is significantly more activated in acquired radioresistant lung cancer cells (i.e., A549-IRR, H358-IRR, and H157-IRR). Higher levels of STAT3 were found to be accumulated in the nucleus of radioresistant lung cancer cells. Niclosamide, a potent STAT3 inhibitor, can reduce STAT3 nuclear localization in radioresistant lung cancer cells. Intriguingly, either inhibition of STAT3 activity by niclosamide or depletion of STAT3 by RNA interference reverses radioresistance in vitro. Niclosamide alone or in combination with radiation overcame radioresistance in lung cancer xenografts. These findings uncover a novel mechanism of radioresistance and provide a more effective approach to overcome radioresistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway, which may potentially improve lung cancer outcome, especially for those patients who have resistance to radiotherapy. Mol Cancer Ther; 13(3); 606–16. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-13-0608
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2062135-8
    detail.hit.zdb_id: 2063563-1
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Small-molecule Bax agonists for cancer therapy
    Springer Science and Business Media LLC ; 2014
    In:  Nature Communications Vol. 5, No. 1 ( 2014-09-17)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2014-09-17)
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/ncomms5935
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
    detail.hit.zdb_id: 2553671-0
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