دورية أكاديمية
Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors.
| العنوان: | Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors. |
|---|---|
| المؤلفون: | Goglia AG; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Delsite R; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Luz AN; High Throughput and Spectroscopy Resource Center, Rockefeller University, New York, New York., Shahbazian D; Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut., Salem AF; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut., Sundaram RK; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut., Chiaravalli J; High Throughput and Spectroscopy Resource Center, Rockefeller University, New York, New York., Hendrikx PJ; Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York., Wilshire JA; Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York., Jasin M; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Kluger HM; Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut., Glickman JF; High Throughput and Spectroscopy Resource Center, Rockefeller University, New York, New York., Powell SN; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. ranjit.bindra@yale.edu powells@mskcc.org., Bindra RS; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut. ranjit.bindra@yale.edu powells@mskcc.org. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2015 Feb; Vol. 14 (2), pp. 326-42. Date of Electronic Publication: 2014 Dec 15. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Drug Screening Assays, Antitumor*, DNA Breaks, Double-Stranded/*drug effects , DNA Repair/*drug effects , High-Throughput Screening Assays/*methods , Radiation-Sensitizing Agents/*pharmacology, Cell Line, Tumor ; Green Fluorescent Proteins/metabolism ; Homologous Recombination/drug effects ; Humans ; Pilot Projects ; Reproducibility of Results ; Small Molecule Libraries/pharmacology |
| مستخلص: | Most cancer therapies involve a component of treatment that inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Complex systems have evolved to repair these lesions, and successful DSB repair is essential for tumor cell survival after exposure to ionizing radiation (IR) and other DNA-damaging agents. As such, inhibition of DNA repair is a potentially efficacious strategy for chemo- and radiosensitization. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) represent the two major pathways by which DSBs are repaired in mammalian cells. Here, we report the design and execution of a high-throughput, cell-based small molecule screen for novel DSB repair inhibitors. We miniaturized our recently developed dual NHEJ and HR reporter system into a 384-well plate-based format and interrogated a diverse library of 20,000 compounds for molecules that selectively modulate NHEJ and HR repair in tumor cells. We identified a collection of novel hits that potently inhibit DSB repair, and we have validated their functional activity in a comprehensive panel of orthogonal secondary assays. A selection of these inhibitors was found to radiosensitize cancer cell lines in vitro, which suggests that they may be useful as novel chemo- and radio sensitizers. Surprisingly, we identified several FDA-approved drugs, including the calcium channel blocker mibefradil dihydrochloride, that demonstrated activity as DSB repair inhibitors and radiosensitizers. These findings suggest the possibility for repurposing them as tumor cell radiosensitizers in the future. Accordingly, we recently initiated a phase I clinical trial testing mibefradil as a glioma radiosensitizer. (©2014 American Association for Cancer Research.) |
| References: | Cancer Res. 2004 Oct 1;64(19):7144-9. (PMID: 15466212) J Med Chem. 2010 Apr 8;53(7):2719-40. (PMID: 20131845) PLoS Genet. 2010 Nov;6(11):e1001194. (PMID: 21079684) Mol Cell Biol. 1984 Jun;4(6):1020-34. (PMID: 6330525) J Exp Med. 1966 Nov 1;124(5):915-9. (PMID: 5926302) Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20902-7. (PMID: 18093953) J Neurooncol. 2013 Jan;111(2):97-102. (PMID: 23086436) Semin Radiat Oncol. 2010 Oct;20(4):217-22. (PMID: 20832013) Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):540-8. (PMID: 20950945) Nat Cell Biol. 2007 Jun;9(6):675-82. (PMID: 17486118) PLoS Genet. 2008 Jun;4(6):e1000110. (PMID: 18584027) Nucleic Acids Res. 2013 Jun;41(11):e115. (PMID: 23585275) Mol Cancer Ther. 2011 Oct;10(10):1949-58. (PMID: 21825006) Radiother Oncol. 2011 Oct;101(1):35-8. (PMID: 21722985) Nat Biotechnol. 2001 Oct;19(10):940-5. (PMID: 11581659) Curr Opin Chem Biol. 2007 Oct;11(5):503-10. (PMID: 17931958) J Exp Med. 1956 May 1;103(5):653-66. (PMID: 13319584) J Exp Med. 2011 Oct 24;208(11):2209-16. (PMID: 21967769) Int J Radiat Oncol Biol Phys. 2009 Aug 1;74(5):1323-31. (PMID: 19616740) Cancer Chemother Pharmacol. 2012 Jan;69(1):155-64. (PMID: 21630086) Genetics. 2007 Aug;176(4):2003-14. (PMID: 17565964) Cell. 2010 Apr 16;141(2):243-54. (PMID: 20362325) Cancer Metastasis Rev. 1995 Mar;14(1):31-41. (PMID: 7606819) Nat Rev Mol Cell Biol. 2014 Jan;15(1):7-18. (PMID: 24326623) J Biomol Screen. 1999;4(2):67-73. (PMID: 10838414) Drugs Today (Barc). 2014 Feb;50(2):159-79. (PMID: 24619591) Pigment Cell Melanoma Res. 2013 Nov;26(6):928-30. (PMID: 23870422) Mol Cell Biol. 2005 Dec;25(24):10842-52. (PMID: 16314509) Methods Mol Biol. 2011;731:219-36. (PMID: 21516411) J Biol Chem. 2008 Jan 4;283(1):1-5. (PMID: 17999957) Nucleic Acids Res. 2006;34(21):6170-82. (PMID: 17088286) Nat Struct Mol Biol. 2009 Aug;16(8):814-8. (PMID: 19633669) Nucleic Acids Res. 2008 May;36(8):2561-9. (PMID: 18332040) J Pharmacol Exp Ther. 2011 Jul;338(1):345-52. (PMID: 21508084) Genes Dev. 1999 Oct 15;13(20):2633-8. (PMID: 10541549) PLoS Genet. 2010 Feb;6(2):e1000855. (PMID: 20195511) Nucleic Acids Res. 2014 May;42(9):5689-701. (PMID: 24682826) Nature. 2011 Mar 10;471(7337):245-8. (PMID: 21390132) DNA Repair (Amst). 2014 May;17:81-97. (PMID: 24613763) Radiat Res. 2006 Oct;166(4):567-74. (PMID: 17007549) J Med Chem. 2012 Apr 12;55(7):3011-20. (PMID: 22380680) J Biomol Screen. 2003 Oct;8(5):566-70. (PMID: 14567784) Science. 1998 Dec 4;282(5395):1893-7. (PMID: 9836640) Curr Drug Targets CNS Neurol Disord. 2004 Apr;3(2):105-11. (PMID: 15078185) Cell Cycle. 2013 Apr 15;12(8):1163-4. (PMID: 23549170) Biochem Pharmacol. 2013 Apr 1;85(7):888-97. (PMID: 23287412) Cell Cycle. 2013 Mar 15;12(6):907-15. (PMID: 23422001) J Biol Chem. 1998 Mar 6;273(10):5858-68. (PMID: 9488723) Nature. 2007 Sep 27;449(7161):483-6. (PMID: 17898768) Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1345-50. (PMID: 15668400) Radiother Oncol. 2002 Sep;64(3):259-73. (PMID: 12242114) Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2473-8. (PMID: 22308491) Radiother Oncol. 1988 Jan;11(1):31-53. (PMID: 3278340) Nucleic Acids Res. 2008 Jul;36(12):4088-98. (PMID: 18539610) Int J Radiat Biol. 1995 Jun;67(6):655-60. (PMID: 7608628) Nat Chem Biol. 2013 Apr;9(4):232-40. (PMID: 23508189) Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15848-53. (PMID: 18840682) ACS Chem Biol. 2011 Jun 17;6(6):628-35. (PMID: 21428443) Nature. 2007 Sep 27;449(7161):478-82. (PMID: 17713479) Nucleic Acids Res. 2010 Oct;38(18):6065-77. (PMID: 20483915) Nucleic Acids Res. 2012 Aug;40(15):7347-57. (PMID: 22573178) Nat Chem Biol. 2008 Feb;4(2):119-25. (PMID: 18176557) Bioorg Med Chem. 2004 Sep 1;12(17):4749-59. (PMID: 15358300) Mol Cell Biol. 2007 May;27(10):3881-90. (PMID: 17353268) EMBO J. 2011 Mar 16;30(6):1079-92. (PMID: 21317870) Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4604-8. (PMID: 22392994) Prog Mol Biol Transl Sci. 2012;110:289-314. (PMID: 22749150) Assay Drug Dev Technol. 2011 Feb;9(1):13-20. (PMID: 21050072) Nucleic Acids Res. 1995 Dec 11;23(23):4836-43. (PMID: 8532526) Annu Rev Genet. 2011;45:247-71. (PMID: 21910633) Methods Mol Med. 2005;110:21-8. (PMID: 15901923) Cancer Res. 2010 Jun 15;70(12):4972-81. (PMID: 20501833) Mol Cancer Res. 2003 Oct;1(12):913-20. (PMID: 14573792) Proc Natl Acad Sci U S A. 2013 May 7;110(19):7720-5. (PMID: 23610439) PLoS One. 2011;6(3):e16501. (PMID: 21408059) Cell Cycle. 2013 Jan 15;12(2):332-45. (PMID: 23255133) J Exp Med. 2007 Jul 9;204(7):1717-27. (PMID: 17606631) Mol Cell. 2010 Oct 22;40(2):179-204. (PMID: 20965415) J Chem Inf Comput Sci. 2000 Mar-Apr;40(2):367-79. (PMID: 10761142) J Neurosurg. 2013 Apr;118(4):830-7. (PMID: 23198803) |
| معلومات مُعتمدة: | R01 GM054668 United States GM NIGMS NIH HHS; UL1 TR000142 United States TR NCATS NIH HHS; R01 CA169306 United States CA NCI NIH HHS; R01 CA081622 United States CA NCI NIH HHS; F31 CA260794 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Radiation-Sensitizing Agents) 0 (Small Molecule Libraries) 147336-22-9 (Green Fluorescent Proteins) |
| تواريخ الأحداث: | Date Created: 20141217 Date Completed: 20151103 Latest Revision: 20220716 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC4326563 |
| DOI: | 10.1158/1535-7163.MCT-14-0765 |
| PMID: | 25512618 |
| قاعدة البيانات: | MEDLINE |
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