Antitumor effect of a novel A3 adenosine receptor agonist, Thio-Cl-IB-MECA, by the induction of cell cycle arrest and apoptosis in human lung cancer cells

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A₃ adenosine receptor (A₃AR) agonists have been shown to inhibit the growth of a variety of human cancer cells. On this line, agonists against A₃AR are considered as novel therapeutic targets for anticancer drug development. Recently, we found 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 also exhibited the growth inhibitory activity in a panel of cancer cell lines.
 The present study investigated the in vitro and in vivo antiproliferative effects and the mechanisms of actions of thio-Cl-IB-MECA in A549 human lung cancer cells. Thio-Cl-IB-MECA induced the arrest of cell cycle progression in the G0/G1 phase at lower concentrations (up to 20 μM) and apoptotic cell death at a higher concentration (80 μM), which were manifested by down-regulation of cyclin D1, c-myc, and cdk4, activation of caspase-3 and -9, and cleavage of poly(ADP-ribose) polymerase (PARP). The activation of Akt-mediated signaling was also inhibited by treatment with thio-Cl-IB-MECA.
 With the potential of thio-Cl-IB-MECA on the inhibition of cancer cell proliferation, we further investigated anti-tumor effect of thio-Cl-IB-MECA (0.02, 0.2, or 2 mg/kg) using an in vivo tumor xenograft model. The compound was given orally once daily for 35 days, starting on day 15 after implantation of A549 human lung cancer cells. Tumors were monitored every 3-5 days and excised from animals on 35 days after inoculation. As a result, thio-Cl-IB-MECA significantly inhibited the tumor growth in A549-xenograft model without any overt side effect. Along with the inhibitory effects on cancer cell proliferation, thio-Cl-IB-MECA might be considered to possess anti-tumor potential. These results suggest that thio-Cl-IB-MECA might be a potential candidate for further developing anticancer agent (This study was supported in part by the grant from Seoul R&BD Program(10541)).