[nhibitory effect of adenosine analogues on invasion of human ovarian cancer cell line HO-8910PM].
OBJECTIVE
Adenosine plays an essential role in cells signal transduction, including inhibiting the activity of phosphatidylinositol 4-kinase, up-regulating the activity of adenylate cyclase and the concentration of cAMP, and inhibiting platelet actin polymerization. Adenosine analogues have the same bioactivities as adenosine, but are slowly deaminated by adenosine deaminase. This study was to observe the effects of 2-chloro-adenosine(2-ClAdo), 2-chloro-2'-deoxyadenosine (2-CldAdo), and 2'-deoxyadenosine (2'-dAdo) on invasion of human ovarian cancer cell line HO-8910PM.


METHODS
HO-8910PM cells were treated with 2-ClAdo, 2-CldAdo, and 2'-dAdo, Trypan blue dye exclusion assay was used to examine cytotoxities of these 3 adenosine analogues to HO-8910PM cells, 5-fluorouracil (5-FU) was used as sensitive control. Reconstituted basement membrane invasion assay was used to evaluate invasive, adhesive, and kinetic activities of the cells. PAGE substrate zymography was used to analyze secretion,and activity of matrix metalloproteinase-9 (MMP-9). Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to analyze mRNA levels of mta1 and nm23H1.


RESULTS
The 50% inhibition concentrations (IC(50)) of 2-ClAdo, and 2-CldAdo at 72 h were 5.80, and 2.61 micromol/L; while inhibitory effect of 2'-dAdo on the cells was not significant, its IC(50) was more than 100 micromol/L. Inhibition rates of 6.0 micromol/L of 2-ClAdo, and 2-CldAdo on cells invasion were (42.5+/-1.5)%, and (9.9+/-0.5)%; those on cells migration were (36.9+/-2.1)%,and (17.1+/-0.4)%; and those on cells adhesion were (32.2+/-2.3)%, and (19.5+/-3.1)%. All these inhibition rates were significantly higher than those of control (P< 0.05). While 2'-dAdo had no significant effect on cells invasion. All 3 chemicals could not inhibit the production and activity of MMP-9 in HO-8910PM cells. 2-ClAdo down-regulated mRNA level of mta1, but neither 2-ClAdo nor 2-CldAdo affected mRNA level of nm23H1.


CONCLUSIONS
Of these 3 adenosine analogues, 2-ClAdo might be a potential chemical inhibiting tumor invasion and metastasis because of its weaker cytotoxity but stronger inhibitive effect on invasion of tumor cells.
Zhu
Feng
F
Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China.
Liu
Xin-Guang
XG
Liang
Nian-Ci
NC
D015762:2-Chloroadenosine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017338:Cladribine / Q000494:pharmacology*; D003839:Deoxyadenosines / Q000494:pharmacology*; D005260:Female; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D054778:NM23 Nucleoside Diphosphate Kinases; D009361:Neoplasm Invasiveness; D009701:Nucleoside-Diphosphate Kinase / Q000096:biosynthesis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators
D000970:Antineoplastic Agents; D003839:Deoxyadenosines; C089320:MTA1 protein, human; D054778:NM23 Nucleoside Diphosphate Kinases; D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators; D015762:2-Chloroadenosine; D017338:Cladribine; D009701:Nucleoside-Diphosphate Kinase; D020780:Matrix Metalloproteinase 9; D006655:Histone Deacetylases; C058118:2'-deoxyadenosine