A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment.
Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical "old drug" aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro. Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6β1, CD44 ,MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers "E-cadherin" and "β-catenin", and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis.
Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China.
Qiao
Q
Tang
Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China.
Yajun
Y
Liu
Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China.
Tao
T
Li
Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China.
Xiang
X
Yang
Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China.
Guirong
G
Zheng
Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China.
Hongning
H
Chen
Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China.
Lee
L
Jia
Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China.
Jingwei
J
Shao
D000818:Animals; D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology*; D015415:Biomarkers; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D000097245:Ursolic Acid
D001241:Aspirin; D015415:Biomarkers; D066246:ErbB Receptors; D012333:RNA, Messenger; D014315:Triterpenes; D000097245:Ursolic Acid
EGFR; EMT; aspirin; cancer metastatic chemoprevention; ursolic acid
Expert Rev Clin Pharmacol. 2015 Jan;8(1):61-75
25363790
Biochem Pharmacol. 2013 Jun 1;85(11):1579-87
23499879
Cochrane Database Syst Rev. 2015 Jul 30;(7):CD001751
26224322
AAPS J. 2014 Mar;16(2):289-98
24442753
J Oncol. 2015;2015:587193
25883652
Life Sci. 2016 Feb 1;146:201-13
26775565
CA Cancer J Clin. 2012 Jul-Aug;62(4):220-41
22700443
Lab Invest. 2015 Jul;95(7):702-17
25867761
Arch Med Res. 2014 Apr;45(3):203-9
24606818
FEBS Lett. 2015 Jun 22;589(14):1577-87
25979173
Cancer Cell. 2009 Mar 3;15(3):195-206
19249678
Biochim Biophys Acta. 2015 Apr;1855(2):254-63
25842298
Biomed Pharmacother. 2009 Aug;63(7):522-7
18849138
Z Rheumatol. 2003 Feb;62(1):80-1
12624808
Prostaglandins Other Lipid Mediat. 2015 Jul;120:91-6
26093284
Sci Rep. 2014 May 21;4:5006
25833312
Oncotarget. 2015 Apr 20;6(11):9295-312
25823660
Inflammation. 2016 Apr;39(2):643-50
26635114
Biophys J. 2008 Jul;95(1):155-65
18339758
Z Naturforsch C. 2006 Nov-Dec;61(11-12):777-82
17294686
Methods Mol Biol. 2014;1070:57-75
24092432
Toxicol In Vitro. 2011 Oct;25(7):1274-80
21539908
Clin Cancer Res. 2012 Sep 15;18(18):4942-53
22832932
Biochem Pharmacol. 2015 Jan 15;93(2):151-62
25522955
Int J Cancer. 2014 Feb 1;134(3):519-29
23852449
Drug Des Devel Ther. 2015 Jul 31;9:3989-4104
26347199
Osteoarthritis Cartilage. 2010 Jun;18(6):849-56
20171296
Cancer Metastasis Rev. 2013 Dec;32(3-4):643-71
23903773
Oncotarget. 2015 May 10;6(13):11465-76
25888636
Carcinogenesis. 2007 Jun;28(6):1153-62
17272306
Mol Vis. 2015 Jun 24;21:706-10
26109834
Cell Adhes Commun. 1998;6(2-3):225-36
9823473
Oncotarget. 2015 May 10;6(13):10697-711
25986923
Chem Biol Drug Des. 2015 Dec;86(6):1397-404
26077799
J Biomed Biotechnol. 2011;2011:567305
22007144
Onco Targets Ther. 2015 Dec 16;8:3783-92
26719706
Oncotarget. 2015 Oct 13;6(31):31659-73
26384307
CA Cancer J Clin. 2015 Jan-Feb;65(1):5-29
25559415
J Oncol. 2015;2015:792182
26425122
J Ethnopharmacol. 2001 May;75(2-3):125-32
11297842
PLoS One. 2012;7(6):e39332
22745735
Tumour Biol. 2016 Feb;37(2):1727-38
26314861
Cochrane Database Syst Rev. 2014 Jun 19;(6):CD003101
24941907
Minerva Med. 2010 Jun;101(3):163-78
20562804
J Clin Diagn Res. 2015 Jan;9(1):XE01-XE03
25738074
Oncotarget. 2015 Nov 3;6(34):35157-72
26459390
Molecules. 2015 Nov 19;20(11):20614-41
26610440
J Cancer Res Ther. 2014 Aug;10 Suppl 1:14-9
25207885
Eur J Med Chem. 2011 Jul;46(7):2652-61
21514015
Sci Rep. 2014 Mar 11;4:4344
24614329
J Cancer Prev. 2015 Dec;20(4):223-31
26734584