A Novel Nitrobenzoate Microtubule Inhibitor that Overcomes Multidrug Resistance Exhibits Antitumor Activity.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • Subject Terms:
      Benzoates/*administration & dosage ; Drug Resistance, Multiple/*drug effects ; Drug Resistance, Neoplasm/*drug effects ; Morpholines/*administration & dosage ; Neoplasms/*drug therapy ; Nitrobenzoates/*administration & dosage ; Tubulin Modulators/*administration & dosage; A549 Cells ; Animals ; Benzoates/chemistry ; Benzoates/pharmacology ; Cell Cycle/drug effects ; Cell Survival/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Regulatory Networks/drug effects ; HT29 Cells ; Humans ; Mice ; Morpholines/chemistry ; Morpholines/pharmacology ; NIH 3T3 Cells ; Neoplasms/genetics ; Nitrobenzoates/chemistry ; Nitrobenzoates/pharmacology ; Tubulin Modulators/chemistry ; Tubulin Modulators/pharmacology ; Xenograft Model Antitumor Assays
    • Abstract:
      Multidrug resistance is a major limitation for microtubule-binding agents in cancer treatment. Here we report a novel microtubule inhibitor (2-morpholin-4-yl-5-nitro-benzoic acid 4-methylsulfanyl-benzyl ester, IMB5046), its cytotoxicity against multidrug-resistant cell lines and its antitumor efficacy in animal models. IMB5046 disrupted microtubule structures in cells and inhibited purified tubulin polymerization in vitro. It bound to the colchicine pocket of tubulin. IMB5046 displayed potent cytotoxicity against multiple tumor cell lines with an IC50 range of 0.037-0.426 μM. Notably, several multidrug-resistant cell lines which were resistant to colchicine, vincristine and paclitaxel remained sensitive to IMB5046. IMB5046 was not a P-glycoprotein substrate. IMB5046 blocked cell cycle at G2/M phase and induced cell apoptosis. Microarray assay indicated that the differentially expressed genes after IMB5046 treatment were highly related to immune system, cell death and cancer. In a mouse xenograft model IMB5046 inhibited the growth of human lung tumor xenograft by 83% at a well-tolerated dose. It is concluded that IMB5046 is a tubulin polymerization inhibitor with novel chemical structure and can overcome multidrug resistance. It is a promising lead compound for cancer chemotherapy, especially for treatment of multidrug-resistant tumors.
    • References:
      Clin Cancer Res. 2015 Mar 15;21(6):1237-9. (PMID: 25770292)
      Oncogene. 2003 Dec 8;22(56):9075-86. (PMID: 14663486)
      Nat Rev Cancer. 2010 Mar;10(3):194-204. (PMID: 20147901)
      Yao Xue Xue Bao. 2006 Dec;41(12):1146-51. (PMID: 17290610)
      Am J Med. 2015 May;128(5):461-70. (PMID: 25554368)
      Cancer Res. 2009 Mar 1;69(5):1910-5. (PMID: 19223556)
      Nature. 2004 Mar 11;428(6979):198-202. (PMID: 15014504)
      Nat Rev Cancer. 2004 Apr;4(4):253-65. (PMID: 15057285)
      Eur J Cancer. 2013 Jan;49(1):245-53. (PMID: 22683167)
      Yao Xue Xue Bao. 1994;29(4):246-51. (PMID: 7976338)
      Cancer Res. 2004 Jul 1;64(13):4621-8. (PMID: 15231674)
      Nat Rev Drug Discov. 2010 Oct;9(10):790-803. (PMID: 20885410)
      Nat Commun. 2014;5:3155. (PMID: 24434687)
      J Clin Oncol. 1999 Mar;17(3):1061-70. (PMID: 10071301)
      Clin Cancer Res. 2005 Jun 1;11(11):4136-43. (PMID: 15930349)
      Nat Rev Drug Discov. 2009 Feb;8(2):111-28. (PMID: 19180105)
      Nature. 2003 Apr 17;422(6933):753-8. (PMID: 12700769)
      Biochem Pharmacol. 2013 Jun 15;85(12):1741-52. (PMID: 23611835)
      Clin Cancer Res. 2010 Apr 1;16(7):2085-94. (PMID: 20332319)
      Pharmacotherapy. 2009 Aug;29(8):954-65. (PMID: 19637949)
      Yao Xue Xue Bao. 1997 Sep;32(9):647-51. (PMID: 11596287)
      Br J Cancer. 2014 Mar 18;110(6):1497-505. (PMID: 24569463)
      Biochemistry. 1993 Dec 14;32(49):13560-5. (PMID: 8257691)
      Clin Toxicol (Phila). 2010 Jun;48(5):407-14. (PMID: 20586571)
      Biomed Pharmacother. 2013 Mar;67(2):164-71. (PMID: 23206754)
      Rheumatology (Oxford). 2006 Mar;45(3):274-82. (PMID: 16188942)
      Bioorg Med Chem. 2014 Sep 15;22(18):5050-9. (PMID: 24650703)
      Clin Cancer Res. 2015 Jun 1;21(11):2445-52. (PMID: 25838395)
      Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42. (PMID: 16493418)
      Cancer Treat Rev. 2014 Jun;40(5):614-25. (PMID: 24560997)
      Mol Biol Cell. 2006 Apr;17(4):2009-20. (PMID: 16452631)
      Cancer Biol Ther. 2007 May;6(5):787-94. (PMID: 17387272)
      Clin Cancer Res. 2008 Oct 1;14(19):6218-27. (PMID: 18829501)
      PLoS One. 2013;8(3):e58953. (PMID: 23554962)
      Cell Death Dis. 2014 Apr 10;5:e1162. (PMID: 24722287)
      J Clin Oncol. 2009 Aug 1;27(22):3611-9. (PMID: 19470941)
      Front Oncol. 2014 Jun 18;4:153. (PMID: 24995158)
      Pharm Res. 2012 Nov;29(11):2943-71. (PMID: 22814904)
    • Accession Number:
      0 (Benzoates)
      0 (IMB5046)
      0 (Morpholines)
      0 (Nitrobenzoates)
      0 (Tubulin Modulators)
    • Publication Date:
      Date Created: 20160812 Date Completed: 20180530 Latest Revision: 20181113
    • Publication Date:
      20231215
    • Accession Number:
      PMC4980604
    • Accession Number:
      10.1038/srep31472
    • Accession Number:
      27510727