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Anticancer Res. 2003 May-Jun;23(3A):2077-83.

Targeting the A3 adenosine receptor for cancer therapy: inhibition of prostate carcinoma cell growth by A3AR agonist.

Author information

1
Can-Fite Biopharma Ltd, Kiryat-Matalon, Laboratory of Clinical and Tumor Immunology, Felsenstein Medical Research Center, Tel-Aviv University Sackler Faculty of Medicine, Rabin Medical Center, Petach-Tikva, Israel. pfishman@post.tau.ac.il

Abstract

BACKGROUND:

Agonists to A3 adenosine receptor (A3AR) were shown to inhibit the growth of various tumor cell types. The present study demonstrates that a synthetic A3AR agonist, 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purine- 9-yl]-N-methyl-beta-D-ribofura-nuronamide (IB-MECA), inhibits the growth of androgen-independent PC-3 prostate human carcinoma cells and illustrates the molecular mechanism involved.

MATERIALS AND METHODS:

PC-3 prostate carcinoma cells were used. Cell growth was examined in vitro by the thymidine incorporation assay and in vivo by inoculating the tumor cells subcutaneously into nude mice and monitoring tumor size. The protein expression level in cells and tumor extracts was tested by Western blot analysis.

RESULTS:

A decrease in the protein expression level of A3AR and the downstream effector PKAc was observed. Consequently, the GSK-3 beta protein level increased, resulting in the destabilization of beta-catenin and the subsequent suppression of cyclin D1 and c-myc expression. IB-MECA treatment also induced down-modulation of the expression of NF-kappa B/p65, known to regulate the transcription of cyclin D1 and c-Myc. This chain of events occurred both in vitro and in vivo and suggests the use of the above-mentioned signaling proteins as markers to predict tumor cell response to A3AR activation.

CONCLUSION:

Taken together, we demonstrated that A3AR activation deregulates the Wnt and the NF-kappa B signaling pathways resulting in the inhibition of prostate carcinoma cell growth.

PMID:
12894581
[Indexed for MEDLINE]

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