S-adenosylmethionine in combination with decitabine shows enhanced anti-cancer effects in repressing breast cancer growth and metastasis.
Animals
Antineoplastic Agents
/ pharmacology
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
DNA Methylation
/ drug effects
Decitabine
/ pharmacology
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Mice, Inbred NOD
Mice, SCID
Neoplasm Metastasis
Reproducibility of Results
S-Adenosylmethionine
/ pharmacology
Transcription, Genetic
/ drug effects
Transcriptome
/ genetics
Xenograft Model Antitumor Assays
DNA methylation
S-adenosylmethionine
breast cancer
epigenome
metastasis
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
17
02
2020
revised:
22
06
2020
accepted:
26
06
2020
pubmed:
29
7
2020
medline:
8
5
2021
entrez:
29
7
2020
Statut:
ppublish
Résumé
Abnormal DNA methylation orchestrates many of the cancer-related gene expression irregularities such as the inactivation of tumour suppressor genes through hypermethylation as well as activation of prometastatic genes through hypomethylation. The fact that DNA methylation abnormalities can be chemically reversed positions the DNA methylation machinery as an attractive target for anti-cancer drug development. However, although in vitro studies suggested that targeting concordantly hypo- and hypermethylation is of benefit in suppressing both oncogenic and prometastatic functions of breast cancer cells, this has never been tested in a therapeutic setting in vivo. In this context, we investigated the combined therapeutic effects of an approved nutraceutical agent S-adenosylmethionine (SAM) and FDA-approved hypomethylating agent decitabine using the MDA-MB-231 xenograft model of breast cancer and found a pronounced reduction in mammary tumour volume and lung metastasis compared to the animals in the control and monotherapy treatment arms. Immunohistochemical assessment of the primary breast tumours showed a significantly reduced expression of proliferation (Ki-67) and angiogenesis (CD31) markers following combination therapy as compared to the control group. Global transcriptome and methylome analyses have revealed that the combination therapy regulates genes from several key cancer-related pathways that are abnormally expressed in breast tumours. To our knowledge, this is the first preclinical study demonstrating the anti-cancer therapeutic potential of using a combination of methylating (SAM) and demethylating agent (decitabine) in vivo. Results from this study provide a molecularly founded rationale for clinically testing a combination of agents targeting the epigenome to reduce the morbidity and mortality from breast cancer.
Identifiants
pubmed: 32720467
doi: 10.1111/jcmm.15642
pmc: PMC7521255
doi:
Substances chimiques
Antineoplastic Agents
0
Decitabine
776B62CQ27
S-Adenosylmethionine
7LP2MPO46S
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10322-10337Subventions
Organisme : CIHR
ID : MOP 130410
Pays : Canada
Organisme : CIHR
ID : PJT-156225
Pays : Canada
Informations de copyright
© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
Références
Curr Opin Investig Drugs. 2002 Apr;3(4):627-33
pubmed: 12090735
Carcinogenesis. 2014 Jan;35(1):138-44
pubmed: 23985780
Carcinogenesis. 2016 Jul;37(7):656-68
pubmed: 27207652
J Biol Chem. 2004 Jul 23;279(30):31735-44
pubmed: 15150277
Am J Clin Nutr. 2002 Nov;76(5):1151S-7S
pubmed: 12418493
Nat Protoc. 2012 Mar 01;7(3):562-78
pubmed: 22383036
Oncogene. 2011 May 5;30(18):2161-72
pubmed: 21242971
PLoS Genet. 2014 Mar 06;10(3):e1004160
pubmed: 24603685
Cancer Res. 2008 Aug 1;68(15):6251-9
pubmed: 18676849
Bioinformatics. 2014 Feb 01;30(3):428-30
pubmed: 24336642
Oncogene. 2002 Aug 12;21(35):5483-95
pubmed: 12154409
Bone Res. 2020 Apr 17;8:18
pubmed: 32337090
Sci Rep. 2017 Oct 27;7(1):14200
pubmed: 29079774
Lancet Oncol. 2009 Mar;10(3):223-32
pubmed: 19230772
Nat Rev Cancer. 2011 Sep 23;11(10):726-34
pubmed: 21941284
Bioinformatics. 2013 Jan 15;29(2):189-96
pubmed: 23175756
Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12815-9
pubmed: 18723680
NPJ Breast Cancer. 2017 Apr 26;3:17
pubmed: 28649657
Neoplasia. 2010 Oct;12(10):778-88
pubmed: 20927316
Br J Pharmacol. 2015 Jun;172(11):2705-15
pubmed: 25134627
Cancer. 2006 Apr 15;106(8):1794-803
pubmed: 16532500
Cancer. 2011 Oct 1;117(19):4424-38
pubmed: 21491416
Oncogene. 2003 Mar 6;22(9):1324-32
pubmed: 12618757
Bioinformatics. 2014 Feb 15;30(4):523-30
pubmed: 24336805
Br J Pharmacol. 2015 Jun;172(11):2769-81
pubmed: 25631332
Sci Rep. 2016 May 24;6:26643
pubmed: 27217294
Cancer Res. 2005 Nov 15;65(22):10413-22
pubmed: 16288032
Neoplasia. 2008 Mar;10(3):266-78
pubmed: 18320071
PLoS One. 2011;6(8):e23372
pubmed: 21858090
Adv Exp Med Biol. 2019;1164:179-196
pubmed: 31576549
Front Pharmacol. 2019 Apr 24;10:385
pubmed: 31068808
Nucleic Acids Res. 2018 Jan 4;46(D1):D950-D955
pubmed: 29088455
Nat Rev Genet. 2016 Sep 15;17(10):630-41
pubmed: 27629931
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Antiviral Res. 1990 Oct-Nov;14(4-5):181-205
pubmed: 2088205
Cell. 2015 Aug 27;162(5):961-73
pubmed: 26317465
J Clin Oncol. 2012 Jul 20;30(21):2670-7
pubmed: 22689805
Nat Biotechnol. 2010 Oct;28(10):1069-78
pubmed: 20944599
Am J Clin Nutr. 2002 Nov;76(5):1158S-61S
pubmed: 12420702
Mol Cancer Ther. 2019 Mar;18(3):632-641
pubmed: 30587557
Cancer Med. 2015 May;4(5):732-44
pubmed: 25619880
J Cell Mol Med. 2020 Sep;24(18):10322-10337
pubmed: 32720467
Trends Cancer. 2017 Aug;3(8):571-582
pubmed: 28780934
Oncotarget. 2017 Dec 26;9(4):5169-5183
pubmed: 29435170
Carcinogenesis. 2014 Nov;35(11):2436-46
pubmed: 25178277
Front Oncol. 2019 Jun 11;9:489
pubmed: 31245293
BMC Cancer. 2018 May 18;18(1):574
pubmed: 29776342
Cancer Res. 2011 Sep 1;71(17):5891-903
pubmed: 21747116
Mol Pharmacol. 1984 May;25(3):436-40
pubmed: 6203026
Cell Host Microbe. 2015 Dec 9;18(6):723-35
pubmed: 26651948
J Clin Invest. 2014 Jan;124(1):56-63
pubmed: 24382390