Purpose: A 3 adenosine receptor (A 3 AR) activation was shown to inhibit the growth of various tumor cells via the down-regulation of nuclear factor B and cyclin D1. To additionally elucidate whether A 3 AR is a specific target, a survey of its expression in tumor versus adjacent normal cells was conducted.Experimental Design: A 3 AR mRNA expression in various tumor tissues was tested in paraffin-embedded slides using reverse transcription-PCR analysis. A comparison with A 3 AR expression in the relevant adjacent normal tissue or regional lymph node metastasis was performed. In addition, A 3 AR protein expression was studied in fresh tumors and was correlated with that of the adjacent normal tissue.Results: Reverse transcription-PCR analysis of colon and breast carcinoma tissues showed higher A 3 AR expression in the tumor versus adjacent non-neoplastic tissue or normal tissue. Additional analysis revealed that the lymph node metastasis expressed even more A 3 AR mRNA than the primary tumor tissue. Protein analysis of A 3 AR expression in fresh tumors derived from colon (n ‫؍‬ 40) or breast (n ‫؍‬ 17) revealed that 61% and 78% had higher A 3 AR expression in the tumor versus normal adjacent tissue, respectively. The high A 3 AR expression level in the tumor tissues was associated with elevated nuclear factor B and cyclin D1 levels. High A 3 AR mRNA expression was also demonstrated in other solid tumor types.Conclusions: Primary and metastatic tumor tissues highly express A 3 AR indicating that high receptor expression is a characteristic of solid tumors. These findings and our previous data suggest A 3 AR as a potential target for tumor growth inhibition.

Objective. Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A 3 adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model.Methods. OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 g/kg given twice daily) was initiated. The A 3 adenosine receptor antagonist MRS1220 (100 g/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O-fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses.Results. CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-B signaling pathway, resulting in down-regulation of tumor necrosis factor ␣. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes.Conclusion. CF101 deregulated the NF-B signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA.Osteoarthritis (OA) is the most common chronic joint disease. Articular cartilage is a major component of the joint, and its mechanical properties depend on the integrity of the extracellular matrix, which is composed mainly of proteoglycans and collagens. Degeneration of joint cartilage is the central feature in OA, but the disease is associated with concomitant changes in synovium and subchondral bone metabolism, causing inflammation of the synovial membrane in the involved joints (1).The cause of OA is multifactorial and includes both systemic and local biomechanical factors (2). Systemic factors that have been associated with OA include age, sex, race-and gene-based susceptibility, bone density, estrogen levels, and nutritional factors. OA results from the failure of chondrocytes that lie within the joint to synthesize a good-quality matrix and to maintain a balance between synthesis and degradation of the extracellular matrix. Synovial inflammation and local concentration of proinflammatory mediators seem to Supported by Can-Fite BioPharma.

The Gi protein-associated A3 adenosine receptor (A3AR) is a member of the adenosine receptor family. Selective agonists at the A3AR, such as CF101 and CF102 were found to induce anti-inflammatory and anti-cancer effects. In this study, we examined the differential effect of CF102 in pathological conditions of the liver. The anti-inflammatory protective effect of CF101 was tested in a model of liver inflammation induced by Concanavalin A (Con. A) and the anti-cancer effect of CF102 was examined in vitro and in a xenograft animal model utilizing Hep-3B hepatocellular carcinoma (HCC) cells. The mechanism of action was explored by following the expression levels of key signaling proteins in the inflamed and tumor liver tissues, utilizing Western blot (WB) analysis. In the liver inflammation model, CF102 (100 μg/kg) markedly reduced the secretion of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase in comparison to the vehicle-treated group. Mechanistically, CF102 treatment decreased the expression level of phosphorylated glycogen synthase kinase-3β, NF-κB, and TNF-α and prevented apoptosis in the liver. This was demonstrated by decreased expression levels of Fas receptor (FasR) and of the pro-apoptotic proteins Bax and Bad in liver tissues. In addition, CF102-induced apoptosis of Hep-3B cells both in vitro and in vivo via de-regulation of the PI3K-NF-κB signaling pathway, resulting in up-regulation of pro-apoptotic proteins. Taken together, CF102 acts as a protective agent in liver inflammation and inhibits HCC tumor growth. These results suggest that CF102 through its differential effect is a potential drug candidate to treat various pathological liver conditions.