Methyl-β-cyclodextrin, an actin depolymerizer augments the antiproliferative potential of microtubule-targeting agents.
Actin Cytoskeleton
/ drug effects
Animals
Antineoplastic Agents
/ pharmacology
Cell Adhesion
Cell Movement
Cell Proliferation
Cytostatic Agents
/ pharmacology
Drug Synergism
Focal Adhesions
/ drug effects
HeLa Cells
Humans
MCF-7 Cells
Mice
Microtubules
/ drug effects
PC-3 Cells
beta-Cyclodextrins
/ pharmacology
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
21 05 2019
21 05 2019
Historique:
received:
07
02
2019
accepted:
02
05
2019
entrez:
23
5
2019
pubmed:
23
5
2019
medline:
21
10
2020
Statut:
epublish
Résumé
Methyl-β-cyclodextrin (MCD), an established pharmacological excipient, depolymerizes the actin cytoskeleton. In this work, we investigated the effect of MCD-mediated actin depolymerization on various cellular phenotypes including traction force, cell stiffness, focal adhesions, and intracellular drug accumulation. In addition to a reduction in the contractile cellular traction, MCD acutely inhibits the maturation of focal adhesions. Alteration of contractile forces and focal adhesions affects the trypsin-mediated detachment kinetics of cells. Moreover, MCD-mediated actin depolymerization increases the intracellular accumulation of microtubule-targeting agents (MTAs) by ~50% with respect to the untreated cells. As MCD treatment enhances the intracellular concentration of drugs, we hypothesized that the MCD-sensitized cancer cells could be effectively killed by low doses of MTAs. Our results in cervical, breast, hepatocellular, prostate cancer and multidrug-resistant breast cancer cells confirmed the above hypothesis. Further, the combined use of MCD and MTAs synergistically inhibits the proliferation of tumor cells. These results indicate the potential use of MCD in combination with MTAs for cancer chemotherapy and suggest that targeting both actin and microtubules simultaneously may be useful for cancer therapy. Importantly, the results provide significant insight into the crosstalk between actin and microtubules in regulating the traction force and dynamics of cell deadhesion.
Identifiants
pubmed: 31113967
doi: 10.1038/s41598-019-43947-4
pii: 10.1038/s41598-019-43947-4
pmc: PMC6529501
doi:
Substances chimiques
Antineoplastic Agents
0
Cytostatic Agents
0
beta-Cyclodextrins
0
methyl-beta-cyclodextrin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7638Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : DBT-Wellcome Trust India Alliance
ID : IA/E/11/1/500419
Pays : India
Références
Biomed Res Int. 2015;2015:198268
pubmed: 26582104
Circ Res. 1982 Nov;51(5):657-61
pubmed: 6890416
Cell Mol Bioeng. 2009 Jun;2(2):218-230
pubmed: 21297858
PLoS One. 2012;7(8):e44311
pubmed: 22952952
Biochemistry. 2008 Dec 9;47(49):13016-25
pubmed: 19049291
Biomater Sci. 2018 May 1;6(5):1109-1119
pubmed: 29528341
J Neurosci Methods. 2002 Mar 30;115(1):97-105
pubmed: 11897369
J Cell Biol. 2010 Jan 25;188(2):287-97
pubmed: 20100912
J Cell Sci. 2011 Dec 15;124(Pt 24):4233-40
pubmed: 22193960
J Biol Chem. 2002 Jul 19;277(29):25867-9
pubmed: 12039946
J Med Chem. 2016 Apr 14;59(7):3439-51
pubmed: 26938120
Trends Cancer. 2017 Jun;3(6):391-406
pubmed: 28670628
Br J Cancer. 1998 Nov;78(9):1165-9
pubmed: 9820174
J Cell Sci. 1993 Feb;104 ( Pt 2):261-74
pubmed: 8505360
Sci Rep. 2018 Aug 17;8(1):12363
pubmed: 30120268
PLoS One. 2014 Sep 24;9(9):e107895
pubmed: 25251154
Cancer Lett. 2002 Apr 25;178(2):209-17
pubmed: 11867206
Cell Physiol Biochem. 2007;20(5):495-506
pubmed: 17762176
J Pharm Sci. 2018 Jul;107(7):1741-1753
pubmed: 29625157
ACS Omega. 2017 Aug 31;2(8):4632-4646
pubmed: 30023727
Microvasc Res. 2009 Jan;77(1):53-63
pubmed: 19028505
Biosci Rep. 2016 Apr 27;36(2):
pubmed: 26980197
Biol Pharm Bull. 2016;39(6):1029-34
pubmed: 27251506
Sci STKE. 2002 Jul 02;2002(139):pe31
pubmed: 12096217
Adv Enzyme Regul. 1984;22:27-55
pubmed: 6382953
Mol Biol Cell. 2011 Nov;22(21):3986-94
pubmed: 21880897
Biochem J. 2004 Mar 1;378(Pt 2):343-51
pubmed: 14616090
Phys Biol. 2011 Feb;8(1):015009
pubmed: 21301071
Sci Rep. 2017 Mar 24;7:44984
pubmed: 28337976
Sci Rep. 2015 Jul 07;5:11853
pubmed: 26149967
Colloids Surf B Biointerfaces. 2017 Jan 1;149:64-71
pubmed: 27721167
Mol Cancer. 2014 Sep 01;13:204
pubmed: 25178635
Biochem Pharmacol. 2017 May 15;132:38-47
pubmed: 28242250
PLoS One. 2014 Sep 08;9(9):e106915
pubmed: 25197799
Biochem Pharmacol. 2019 May;163:32-45
pubmed: 30710515
J Natl Cancer Inst. 1990 Jul 4;82(13):1107-12
pubmed: 2359136
Cancer Res. 2013 Aug 15;73(16):5169-82
pubmed: 23946473
J Biol Chem. 2013 Aug 2;288(31):22516-26
pubmed: 23798680
Sci Rep. 2013;3:1104
pubmed: 23346361
Trends Cell Biol. 2016 Aug;26(8):569-576
pubmed: 27133808
Cancer Res. 2002 Dec 1;62(23):6864-9
pubmed: 12460900
J Pharmacol Exp Ther. 2007 Feb;320(2):853-64
pubmed: 17099073
Cytoskeleton (Hoboken). 2011 Dec;68(12):653-60
pubmed: 22083950
Am J Physiol Cell Physiol. 2002 Mar;282(3):C595-605
pubmed: 11832345
J Pharm Sci. 1996 Oct;85(10):1017-25
pubmed: 8897265