The antitumor effect of LJ-529, a novel agonist to A3 adenosine receptor, in both estrogen receptor-positive and estrogen receptor-negative human breast cancers.
Agonists to A3 adenosine receptor (A3AR) have been reported to inhibit cell growth and/or induce apoptosis in various tumors. We tested the effect of a novel A3AR agonist generically known as LJ-529 in breast cancer cells. Anchorage-dependent cell growth and in vivo tumor growth were attenuated by LJ-529, independently of its estrogen receptor (ER) alpha status. In addition, apoptosis was induced as evidenced by the activation of caspase-3 and c-poly(ADP)ribose polymerase. Furthermore, the Wnt signaling pathway was down-regulated and p27(kip) was induced by LJ-529. In ER-positive cells, the expression of ER was down-regulated by LJ-529, which might have additionally contributed to attenuated cell proliferation. In ER-negative, c-ErbB2-overexpressing SK-BR-3 cells, the expression of c-ErbB2 and its downstream extracellular signal-regulated kinase pathway were down-regulated by LJ-529. However, such effect of LJ-529 acted independently of its receptor because no A3AR was detected by reverse transcription-PCR in all four cell lines tested. In conclusion, our novel findings open the possibility of LJ-529 as an effective therapeutic agent against both ER-positive and ER-negative breast cancers, particularly against the more aggressive ER-negative, c-ErbB2-overexpressing types.
Department of Pathology, College of Medicine, Hanyang University, 133-791 Seoul, Republic of Korea.
Heekyoung
H
Chung
Ji-Youn
JY
Jung
Sung-Dae
SD
Cho
Kyung-A
KA
Hong
Hyun-Jun
HJ
Kim
Dong-Hui
DH
Shin
Hwan
H
Kim
Hea Ok
HO
Kim
Dae Hong
DH
Shin
Hyuk Woo
HW
Lee
Lak Shin
LS
Jeong
Gu
G
Kong
D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058909:Adenosine A3 Receptor Agonists; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013872:Thionucleosides / Q000627:therapeutic use*; D051153:Wnt Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000241:Adenosine; D058909:Adenosine A3 Receptor Agonists; D000970:Antineoplastic Agents; D053148:Caspase 3; D020169:Caspases; D050760:Cyclin-Dependent Kinase Inhibitor p27; D047628:Estrogen Receptor alpha; D011065:Poly(ADP-ribose) Polymerases; D018719:Erb-b2 Receptor Tyrosine Kinases; D013872:Thionucleosides; D051153:Wnt Proteins; C510478:2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyl-4'-thioadenosine; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse