c-Jun-NH2-kinase-1 Inhibition Leads to Antitumor Activity in Ovarian Cancer
Pablo E. Vivas‐MejíaAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaJuliana M. BenitoAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaAriel FernándezAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaHee‐Dong HanAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaLingegowda S. MangalaAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaCristian Rodriguez‐AguayoAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaArturo Chávez‐ReyesAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaYvonne G. LinAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaMark CareyAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaAlpa M. NickAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaRebecca L. StoneAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaHye Sun KimAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaFrançois-Xavier ClaretAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaWilliam G. BornmannAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaBryan T. HennessyAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaÁngela SanguinoAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaZhengong PengAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaAnil K. SoodAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, CanadaGabriel Lopez‐BeresteinAuthors' Affiliations: Departments of 1Experimental Therapeutics, 2Gynecologic Oncology, 3Systems Biology, 4Cancer Biology, and 5Center for RNAi and non-coding-RNA, University of Texas M. D. Anderson Cancer Center; and 6Department of Bioengineering and Division of Applied Physics, Rice University, Houston, Texas; 7University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico; 8Centro de Investigación y de Estudios Avanzados del IPN, Unidad Monterrey, PIIT, Apodaca NL, Mexico; and 9Division of Gynecologic Oncology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada
2009en
ABI
Annotatsiya
PURPOSE: To show the functional, clinical, and biological significance of c-Jun-NH(2)-kinase (JNK)-1 in ovarian carcinoma. EXPERIMENTAL DESIGN: Analysis of the impact of JNK on 116 epithelial ovarian cancers was conducted. The role of JNK in vitro and in experimental models of ovarian cancer was assessed. We studied the role of N-5-[4-(4-methyl piperazine methyl)-benzoylamido]-2-methylphenyl-4-[3-(4-methyl)-pyridyl]-2-pyrimidine amine (WBZ_4), a novel JNK inhibitor redesigned from imatinib based on targeting wrapping defects, in cell lines and in experimental models of ovarian cancer. RESULTS: We found a significant association of pJNK with progression-free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose-dependent fashion in four ovarian cancer cell lines. In vivo, whereas imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The antitumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights compared with nonsilencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition. CONCLUSIONS: These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the redesigned WBZ_4 compound should be considered for further clinical development.
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