Human A3
adenosine receptor (A3AR) agonists have been shown to play important roles in several physiological and
pathological processes, including growth inhibition of human
cancer cells. On this line, we recently found that a novel
adenosine analog, 2-chloro-N6-(3-iodobenzyl)-4'-thioadenosine-5'-N-methyluronamide (
thio-Cl-IB-MECA) was a potent human A3AR agonist, and is superior to a known agonist Cl-
IB-MECA [Jeong LS, Jin DZ, Kim HO, Shin DH, Moon HR, Gunaga P, et al. J Med Chem 2003;46:3775]. Here, we report that a novel A3AR agonist,
thio-Cl-IB-MECA inhibited the growth of human promyelocytic
leukemia HL-60 cells by arresting cell cycle and induction of apoptosis.
Thio-Cl-IB-MECA induced the cell cycle arrest of G0/G1 in the early time and at lower concentration (up to 25 microM). At higher concentration (50 microM), the apoptotic cell deaths were manifested by observation of the increase of sub-G0 phase of cell cycle distribution, DNA fragmentation and
poly(ADP-ribose) polymerase (PARP) cleavage. In addition, the down-regulation of checkpoint
protein cyclin D1 and c-myc by
thio-Cl-IB-MECA was well correlated with the arrest of cell cycle transition of G1 to S phase. Further study revealed that the growth inhibitory activity of
thio-Cl-IB-MECA is also related with the modulation of Wnt signaling pathway. The levels of
beta-catenin, phosphorylated forms of GSK-beta and Akt were down-regulated by the treatment of
thio-Cl-IB-MECA (10 nM) in a time-dependent manner, providing one of plausible mechanistic evidence for the involvement of the Wnt signaling pathway in the HL-60 cell growth inhibitory effects by
thio-Cl-IB-MECA. These results suggest that a novel A3AR agonist,
thio-Cl-IB-MECA can down-regulate Wnt signaling, inhibit proliferation and induce apoptosis in HL-60
leukemia cells, and thus provide the possibility of this compound in the potential therapeutic value of the treatment of
leukemia.