Therapeutic efficacy of a novel βIII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer.
Animals
Apoptosis
/ drug effects
Carcinogenesis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Humans
Mice
Neoplasm Metastasis
Paclitaxel
/ administration & dosage
Pancreatic Neoplasms
/ drug therapy
Tubulin
/ drug effects
Tubulin Modulators
/ administration & dosage
Xenograft Model Antitumor Assays
Pancreatic cancer
VERU-111
miR-200c
β –tubulins
βIII/βIV-tubulin inhibitor
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
23 Jan 2019
23 Jan 2019
Historique:
received:
31
08
2018
accepted:
17
12
2018
entrez:
25
1
2019
pubmed:
25
1
2019
medline:
19
4
2019
Statut:
epublish
Résumé
The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, βIII and βIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available. We determined anti-cancer molecular mechanisms and therapeutic efficacy of a novel small molecule inhibitor (VERU-111) using in vitro (MTS, wound healing, Boyden chamber and real-time xCELLigence assays) and in vivo (xenograft studies) models of PanCa. The effects of VERU-111 treatment on the expression of β-tubulin isoforms, apoptosis, cancer markers and microRNAs were determined by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses. We have identified a novel small molecule inhibitor (VERU-111), which preferentially represses clinically important, βIII and βIV tubulin isoforms via restoring the expression of miR-200c. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis - associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also inhibited tumor growth (P < 0.01) in a PanCa xenograft mouse model. This study has identified an inhibitor of βIII/βIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.
Sections du résumé
BACKGROUND
BACKGROUND
The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, βIII and βIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available.
METHODS
METHODS
We determined anti-cancer molecular mechanisms and therapeutic efficacy of a novel small molecule inhibitor (VERU-111) using in vitro (MTS, wound healing, Boyden chamber and real-time xCELLigence assays) and in vivo (xenograft studies) models of PanCa. The effects of VERU-111 treatment on the expression of β-tubulin isoforms, apoptosis, cancer markers and microRNAs were determined by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses.
RESULTS
RESULTS
We have identified a novel small molecule inhibitor (VERU-111), which preferentially represses clinically important, βIII and βIV tubulin isoforms via restoring the expression of miR-200c. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis - associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also inhibited tumor growth (P < 0.01) in a PanCa xenograft mouse model.
CONCLUSIONS
CONCLUSIONS
This study has identified an inhibitor of βIII/βIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.
Identifiants
pubmed: 30674344
doi: 10.1186/s13046-018-1009-7
pii: 10.1186/s13046-018-1009-7
pmc: PMC6343279
doi:
Substances chimiques
TUBB3 protein, human
0
Tubulin
0
Tubulin Modulators
0
Paclitaxel
P88XT4IS4D
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
29Subventions
Organisme : NCI NIH HHS
ID : R01 CA204552
Pays : United States
Organisme : Ministry of Primary Industries
ID : NCI R01CA148706
Organisme : NCI NIH HHS
ID : R01 CA210192
Pays : United States
Organisme : National Institutes of Health
ID : CA21019201
Organisme : NCI NIH HHS
ID : R01 CA206069
Pays : United States
Organisme : National Institutes of Health
ID : CA20455201
Références
Cell Death Differ. 2000 Jan;7(1):102-11
pubmed: 10713725
Clin Breast Cancer. 2002 Dec;3(5):341-5
pubmed: 12533264
Science. 2004 Jul 30;305(5684):626-9
pubmed: 15286356
Clin Cancer Res. 2005 Jan 1;11(1):298-305
pubmed: 15671559
FASEB J. 2005 Aug;19(10):1299-301
pubmed: 15946994
Clin Cancer Res. 2005 Aug 1;11(15):5481-6
pubmed: 16061864
J Biol Chem. 1992 Jul 5;267(19):13335-9
pubmed: 1618835
Histopathology. 2007 Oct;51(4):539-46
pubmed: 17714470
Br J Cancer. 2008 Feb 12;98(3):523-8
pubmed: 18231106
Lancet Oncol. 2008 Feb;9(2):168-75
pubmed: 18237851
Cell. 1991 Mar 8;64(5):903-14
pubmed: 1825803
Nature. 1991 May 16;351(6323):242-5
pubmed: 1828290
Biochemistry. 2008 Jul 15;47(28):7572-82
pubmed: 18570381
Cancer Res. 2008 Dec 1;68(23):9817-24
pubmed: 19047161
Anticancer Agents Med Chem. 2008 Dec;8(8):832-6
pubmed: 19075565
Trends Cell Biol. 2009 Mar;19(3):89-98
pubmed: 19168356
Mol Cancer Ther. 2009 May;8(5):1055-66
pubmed: 19435871
Nat Rev Cancer. 2010 Mar;10(3):194-204
pubmed: 20147901
Methods Cell Biol. 2010;95:47-58
pubmed: 20466129
J Med Chem. 2010 Oct 28;53(20):7414-27
pubmed: 20919720
Mutat Res. 2011 Jul-Oct;728(1-2):23-34
pubmed: 21605699
Bioorg Med Chem. 2011 Aug 15;19(16):4782-95
pubmed: 21775150
Mol Cancer Ther. 2012 Jan;11(1):24-33
pubmed: 22027689
Cancer Discov. 2012 Mar;2(3):260-269
pubmed: 22585996
J Med Chem. 2012 Aug 23;55(16):7285-9
pubmed: 22783954
Gastroenterol Res Pract. 2012;2012:781765
pubmed: 23125850
Expert Opin Ther Targets. 2013 Apr;17(4):461-72
pubmed: 23379899
Med Oncol. 2013 Jun;30(2):545
pubmed: 23532817
Front Plant Sci. 2014 Oct 07;5:511
pubmed: 25339962
Oncotarget. 2015 Feb 10;6(4):2235-49
pubmed: 25544769
World J Gastroenterol. 2015 Mar 21;21(11):3157-65
pubmed: 25805920
Cancer Res. 2015 Jun 1;75(11):2292-304
pubmed: 25840985
Biochem Biophys Res Commun. 2015 Oct 23;466(3):493-8
pubmed: 26375501
Expert Opin Ther Pat. 2016;26(1):1-20
pubmed: 26651178
CA Cancer J Clin. 2016 Jan-Feb;66(1):7-30
pubmed: 26742998
Anticancer Agents Med Chem. 2016;16(10):1325-38
pubmed: 26899186
Neoplasia. 2016 Dec;18(12):753-764
pubmed: 27889644
Cancer Lett. 2017 Mar 1;388:292-302
pubmed: 28025102
Mol Cancer Ther. 2017 Oct;16(10):2267-2280
pubmed: 28615299
Int J Mol Sci. 2017 Jul 04;18(7):null
pubmed: 28677634
Cancers (Basel). 2017 Nov 16;9(11):null
pubmed: 29144412
Oncogenesis. 2018 Feb 22;7(2):19
pubmed: 29467405
Cancers (Basel). 2018 Mar 07;10(3):null
pubmed: 29518944
Environ Health Perspect. 1993 Dec;101 Suppl 5:9-14
pubmed: 8013430
J Biol Chem. 1994 Apr 8;269(14):10324-9
pubmed: 8144613
Cancer Res. 1996 Jun 1;56(11):2584-9
pubmed: 8653701
Semin Oncol. 1997 Apr;24(2 Suppl 7):S7-64-S7-68
pubmed: 9194483
J Clin Oncol. 1997 Jun;15(6):2403-13
pubmed: 9196156
Eur J Biochem. 1997 Jun 1;246(2):420-4
pubmed: 9208933
J Clin Invest. 1997 Sep 1;100(5):1282-93
pubmed: 9276747
Curr Opin Cell Biol. 1997 Dec;9(6):807-14
pubmed: 9425345
Br J Cancer. 1998 Feb;77(4):562-6
pubmed: 9484812