Harish Arie, Hohana Gil, Fishman Pnina, Arnon Oshra, Bar-Yehuda Sara
Department of Surgery A/B and Pathology, Rabin Medical Center, Campus Golda, Sackler Faculty of Medicine, Tel-Aviv University, Petach-Tikva 49100, Israel.
Int J Oncol. 2003 Oct;23(4):1245-9.
Activation of the Gi-protein-coupled A3 adenosine receptor (A3AR) has been reported to be involved in the inhibition of tumor cell growth. A3AR is highly expressed in tumor cells whereas lower expression was noted in a variety of normal cells. Recently we showed that A3AR activation in melanoma cells resulted in growth inhibition via a direct anti-proliferative effect which entailed cell cycle arrest in the G0/G1 and down-regulation of cyclin D1 and c-Myc. In the present study we present an additional mechanism demonstrating that A3AR agonists activate natural killer (NK) cells which further enhance the anti-tumor effect of this group of molecules. NK cells mediate the natural cytotoxicity and their number and function is reduced in cancer patients. We show Cl-IB-MECA to inhibit tumor development via the activation of NK cells is an additional mechanism which accounts for the anti-tumor effect of A3AR agonists. This effect was noted at a low dose of 10 micro g/kg, demonstrating that the response is exclusively A3AR mediated. Treatment of naïve mice for four days yielded the highest effect on NK cell potentiation. In mice inoculated with B16-F10 melanoma cells and treated each orally with Cl-IB-MECA, melanoma growth inhibition correlated with higher serum level of IL-12 and potentiation of NK cells. Moreover, in adoptive transfer experiments in melanoma bearing mice, marked inhibition of lung metastatic foci was noted upon engraftment with splenocytes derived from Cl-IB-MECA treated mice. Taken together, the ability of Cl-IB-MECA to inhibit tumor development via the activation of NK cells is an additional mechanism which accounts for the anti-tumor effect of A3AR agonists.
据报道，Gi蛋白偶联的A3腺苷受体（A3AR）的激活与肿瘤细胞生长的抑制有关。A3AR在肿瘤细胞中高表达，而在多种正常细胞中表达较低。最近我们发现，黑色素瘤细胞中A3AR的激活通过直接的抗增殖作用导致生长抑制，这需要细胞周期停滞在G0/G1期，并下调细胞周期蛋白D1和c-Myc。在本研究中，我们提出了另一种机制，证明A3AR激动剂可激活自然杀伤（NK）细胞，从而进一步增强这组分子的抗肿瘤作用。NK细胞介导自然细胞毒性，癌症患者的NK细胞数量和功能会降低。我们发现Cl-IB-MECA通过激活NK细胞来抑制肿瘤发展是A3AR激动剂抗肿瘤作用的另一种机制。在低至10μg/kg的剂量下即可观察到这种效应，表明该反应完全由A3AR介导。对未处理的小鼠进行四天的治疗对NK细胞的增强作用最为显著。在用B16-F10黑色素瘤细胞接种并每天口服Cl-IB-MECA治疗的小鼠中，黑色素瘤生长抑制与血清中IL-12水平升高和NK细胞增强有关。此外，在黑色素瘤荷瘤小鼠的过继转移实验中，移植来自Cl-IB-MECA处理小鼠的脾细胞后，肺部转移灶受到明显抑制。综上所述，Cl-IB-MECA通过激活NK细胞抑制肿瘤发展是A3AR激动剂抗肿瘤作用的另一种机制。
