دورية أكاديمية
أعرض في EDS

Impact of kinesin Eg5 inhibition by 3,4-dihydropyrimidin-2(1H)-one derivatives on various breast cancer cell features.

التفاصيل البيبلوغرافية
العنوان: Impact of kinesin Eg5 inhibition by 3,4-dihydropyrimidin-2(1H)-one derivatives on various breast cancer cell features.
المؤلفون: Guido BC; Department of Cell Biology, Laboratory of Electron Microscopy, University of Brasília (IB-UnB), Campus Universitário Darcy Ribeiro, Brasília, DF, Brazil. brunacguido@gmail.com., Ramos LM; Laboratory of Medicinal and Technological Chemistry, University of Brasília (IQ-UnB), Brasília, Distrito Federal, Brazil. lucianamramos@hotmail.com., Nolasco DO; Research Laboratory of Electronics, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. nolasco@mit.edu.; Physics Course, Catholic University of Brasília, Brasília, Distrito Federal, Brazil. nolasco@mit.edu., Nobrega CC; Department of Cell Biology, Laboratory of Electron Microscopy, University of Brasília (IB-UnB), Campus Universitário Darcy Ribeiro, Brasília, DF, Brazil. catharine_carrara@hotmail.com., Andrade BY; Department of Cell Biology, Laboratory of Electron Microscopy, University of Brasília (IB-UnB), Campus Universitário Darcy Ribeiro, Brasília, DF, Brazil. barbarayasmi@gmail.com., Pic-Taylor A; Laboratory of Embryology and Developmental Biology, Genetics and Morphology Department, University of Brasília (IB-UnB), Brasília, Distrito Federal, Brazil. alinepic@unb.br., Neto BA; Laboratory of Medicinal and Technological Chemistry, University of Brasília (IQ-UnB), Brasília, Distrito Federal, Brazil. brenno.ipi@gmail.com., Corrêa JR; Department of Cell Biology, Laboratory of Electron Microscopy, University of Brasília (IB-UnB), Campus Universitário Darcy Ribeiro, Brasília, DF, Brazil. correa@unb.br.
المصدر: BMC cancer [BMC Cancer] 2015 Apr 14; Vol. 15, pp. 283. Date of Electronic Publication: 2015 Apr 14.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 100967800 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2407 (Electronic) Linking ISSN: 14712407 NLM ISO Abbreviation: BMC Cancer Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : BioMed Central, [2001-
مواضيع طبية MeSH: Kinesins/*antagonists & inhibitors , Pyrimidines/*pharmacology, Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Female ; Humans ; Inhibitory Concentration 50 ; Kinesins/chemistry ; Models, Molecular ; Molecular Conformation ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neovascularization, Pathologic ; Pyrimidines/chemical synthesis ; Pyrimidines/chemistry ; Time Factors
مستخلص: Background: Breast cancer is a complex heterogeneous disease and is one of the leading causes of death among women. In addressing the need for treatments of this life-threatening illness, we studied 3,4-dihydropyrimidin-2(1H)-one (or thione) derivatives (DHPMs), a class of inhibitor molecules of the Eg5 motor spindle protein that shows pronounced antitumor activity against several cancer cell lines.
Methods: An in vitro screening was performed for identification of DHPMs with potent antitumor effects on MCF-7 and MDA-MB-231 cells and the selected DHPMs were evaluated for their inhibitory activity on Eg5 both in silico, using Molecular dynamics, and in vitro Eg5 inhibition assays. Analysis of cell death induction, proliferation, cell cycle and cancer stem cells (CSC) profile were performed by flow cytometry to assess the influence of the selected DPHMs on these important tumor features. Finally, the effects of DHPM treatment on tube formation were evaluated in vitro using HUVEC cells, and in vivo using a model on chorioallantoic membrane (CAM) of fertilized eggs.
Results: We identified five DHPMs with pronounced inhibitory activity on Eg5 motor protein interfering with the proper mitotic spindle assembly during cell division. These compounds impair the correct conclusion of cell cycle of the breast cancer cells and showed to be selective for tumor cells. Moreover, DHPMs modulate the CD44(+)/CD24(-) phenotype leading to a decrease in the CSC population in MDA-MB-231 cells, an important effect since CSC are resistant to many conventional cancer therapies and play a pivotal role in tumor initiation and maintenance. This observation was confirmed by the results which demonstrated that DHPM treated cells had impaired proliferation and were unable to sustain angiogenesis events. Finally, the DHMP treated cells were induced to apoptosis, which is one of the most pursued goals in drug development.
Conclusions: The results of our study strongly suggest that DHPMs inhibit important tumorigenic features of breast cancer cells leading them to death by apoptosis. These findings firmly point to DHPM molecular architecture as a promising alternative against breast cancer.
References: Int J Mol Sci. 2013;14(8):17157-67. (PMID: 23965978)
Acta Pharmacol Sin. 2011 Dec;32(12):1543-8. (PMID: 21986572)
Eur J Med Chem. 2013 Apr;62:614-31. (PMID: 23434636)
Bioorg Med Chem Lett. 2014 Aug 15;24(16):3961-3. (PMID: 25001485)
Cancer Cell. 2013 Sep 9;24(3):347-64. (PMID: 24029232)
ACS Chem Biol. 2015 Apr 17;10(4):1128-36. (PMID: 25622007)
Cell. 2010 Jan 8;140(1):62-73. (PMID: 20074520)
Curr Cancer Drug Targets. 2015;15(3):256-69. (PMID: 25669721)
Nat Rev Mol Cell Biol. 2011 Jun;12(6):385-92. (PMID: 21527953)
J Cell Biol. 2001 Sep 17;154(6):1125-33. (PMID: 11564753)
Anticancer Res. 2014 Apr;34(4):1837-42. (PMID: 24692717)
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13820-5. (PMID: 19666588)
Proteins. 1993 Dec;17(4):412-25. (PMID: 8108382)
Biochem Pharmacol. 2010 Mar 15;79(6):864-72. (PMID: 19896928)
Eur J Med Chem. 2011 Aug;46(8):3274-81. (PMID: 21620531)
Curr Pain Headache Rep. 2008 Jun;12(3):165-74. (PMID: 18796265)
Science. 1999 Oct 29;286(5441):971-4. (PMID: 10542155)
Cell Stem Cell. 2007 Nov;1(5):555-67. (PMID: 18371393)
Biotechnol Adv. 2014 Nov 1;32(6):1111-22. (PMID: 24681093)
Cell. 2011 Nov 23;147(5):992-1009. (PMID: 22118458)
J Clin Pathol. 2011 Nov;64(11):937-46. (PMID: 21680574)
Mol Cancer Res. 2006 Jul;4(7):457-69. (PMID: 16849521)
Curr Biol. 2001 Sep 18;11(18):1462-7. (PMID: 11566107)
Curr Opin Pharmacol. 2001 Aug;1(4):370-7. (PMID: 11710735)
J Cell Biol. 2000 Sep 4;150(5):975-88. (PMID: 10973989)
Nat Rev Drug Discov. 2009 Oct;8(10):806-23. (PMID: 19794444)
Cell Cycle. 2009 Apr 1;8(7):1030-5. (PMID: 19270519)
Chemistry. 2013 Mar 25;19(13):4156-68. (PMID: 23460474)
Leukemia. 2009 Oct;23(10):1755-62. (PMID: 19458629)
Cancer Res. 2008 Jul 15;68(14):5533-9. (PMID: 18632604)
Curr Opin Cell Biol. 2007 Feb;19(1):75-81. (PMID: 17188855)
CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29. (PMID: 22237781)
Cancer Growth Metastasis. 2015 Jan 29;8:1-13. (PMID: 25674014)
Curr Top Dev Biol. 2014;108:121-51. (PMID: 24512708)
N Engl J Med. 2006 Sep 21;355(12):1253-61. (PMID: 16990388)
Clin Transl Oncol. 2013 Jan;15(1):46-54. (PMID: 22855175)
Nat Rev Cancer. 2009 Apr;9(4):274-84. (PMID: 19308067)
Oncogene. 2004 Apr 12;23(16):2825-37. (PMID: 15077146)
Nature. 2001 Nov 1;414(6859):105-11. (PMID: 11689955)
Tumour Biol. 2015 Jul;36(7):5369-76. (PMID: 25680407)
Cancer Chemother Pharmacol. 2007 Feb;59(2):157-64. (PMID: 16703323)
Mol Cancer Ther. 2004 Sep;3(9):1079-90. (PMID: 15367702)
Org Biomol Chem. 2014 Jun 7;12(21):3427-40. (PMID: 24752551)
J Biochem. 2014 Mar;155(3):195-206. (PMID: 24334276)
Trends Cell Biol. 2005 Sep;15(9):467-76. (PMID: 16084724)
Environ Health Perspect. 1993 Apr;100:9-20. (PMID: 8354184)
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8. (PMID: 12629218)
Oncology (Williston Park). 2014 Dec;28(12):1101-7, 1110. (PMID: 25510809)
Methods Mol Biol. 2012;843:47-57. (PMID: 22222520)
Cell. 2009 Aug 21;138(4):645-59. (PMID: 19682730)
Biotechniques. 2002 Dec;33(6):1244-8. (PMID: 12503308)
Bioorg Chem. 2006 Aug;34(4):173-82. (PMID: 16765411)
Invest New Drugs. 2012 Aug;30(4):1379-88. (PMID: 21655917)
Cancer Res. 2009 Feb 15;69(4):1302-13. (PMID: 19190339)
Cell Death Differ. 2009 Jan;16(1):3-11. (PMID: 18846107)
Clin Dev Immunol. 2012;2012:708036. (PMID: 22693526)
Annu Rev Med. 2007;58:267-84. (PMID: 17002552)
J Chem Theory Comput. 2008 Mar;4(3):435-47. (PMID: 26620784)
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (KIF11 protein, human)
0 (Pyrimidines)
EC 3.6.4.4 (Kinesins)
تواريخ الأحداث: Date Created: 20150418 Date Completed: 20160627 Latest Revision: 20211203
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC4411898
DOI: 10.1186/s12885-015-1274-1
PMID: 25885813
قاعدة البيانات: MEDLINE
الوصف
تدمد:1471-2407
DOI:10.1186/s12885-015-1274-1