2-chloro-n(6)-(3-iodobenzyl)adenosine-5--n-methyluronamide and Liver-Neoplasms

The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC.. The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives.. Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102.. CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.

Topics: Adenosine; Adult; Aged; Apoptosis; Carcinoma, Hepatocellular; Child; Female; Humans; Leukocytes, Mononuclear; Liver Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Purinergic P1 Receptor Agonists; Receptor, Adenosine A3; Sorafenib; Wnt Signaling Pathway

Specific A3 adenosine receptor (A3AR) agonist, 2‑chloro‑N6‑(3‑iodobenzyl)‑5'‑N‑methylcarboxamidoadenosine (2‑Cl‑IB‑MECA), demonstrates anti‑proliferative effects on various types of tumor. In the present study, the cytotoxicity of 2‑Cl‑IB‑MECA was analyzed in a panel of tumor and non‑tumor cell lines and its anticancer mechanisms in JoPaca‑1 pancreatic and Hep‑3B hepatocellular carcinoma cell lines were also investigated. Initially, decreased tumor cell proliferation, cell accumulation in the G1 phase and inhibition of DNA and RNA synthesis was found. Furthermore, western blot analysis showed decreased protein expression level of β‑catenin, patched1 (Ptch1) and glioma‑associated oncogene homolog zinc finger protein 1 (Gli1), which are components of the Wnt/β‑catenin and Sonic hedgehog/Ptch/Gli transduction pathways. In concordance with these findings, the protein expression levels of cyclin D1 and c‑Myc were reduced. Using a luciferase assay, it was revealed for the first time a decrease in β‑catenin transcriptional activity, as an early event following 2‑Cl‑IB‑MECA treatment. In addition, the protein expression levels of multidrug resistance‑associated protein 1 and P‑glycoprotein (P‑gp) were reduced and the P‑gp xenobiotic efflux function was also reduced. Next, the enhancing effects of 2‑Cl‑IB‑MECA on the cytotoxicity of conventional chemotherapy was investigated. It was found that 2‑Cl‑IB‑MECA enhanced carboplatin and doxorubicin cytotoxic effects in the JoPaca‑1 and Hep‑3B cell lines, and a greater synergy was found in the highly tumorigenic JoPaca‑1 cell line. This provides a novel

Topics: Adenosine; Cell Line; Cell Line, Tumor; Cell Proliferation; Drug Resistance; Hedgehog Proteins; Humans; Liver Neoplasms; Pancreatic Neoplasms; Zinc Finger Protein GLI1

The Gi protein-associated A(3) adenosine receptor (A(3) AR) is a member of the adenosine receptor family. Selective agonists at the A(3) AR, 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.

Topics: Adenosine; Adenosine A3 Receptor Agonists; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Concanavalin A; Hepatitis; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Receptor, Adenosine A3; Signal Transduction; Xenograft Model Antitumor Assays

The A3 adenosine receptor (A(3)AR) is highly expressed in tumors and was suggested as a target for cancer treatment. In this study, we show that A(3)AR is highly expressed in tumor tissues and in peripheral blood mononuclear cells (PBMCs) derived from patients with HCC, as well as from HCC tumor-bearing rats. The high expression level of the receptor was directly correlated to overexpression of NF-kappaB, known as a transcription factor of A(3)AR. CF102, a synthetic highly selective agonist to A(3)AR induced a marked dose response inhibition of tumor growth in N1S1 HCC tumor rats, via de-regulation of the NF-kappaB and the Wnt signal transduction pathways, resulting in apoptosis of tumor cells. Taken together, A(3)AR is highly expressed in tumors and PBMCs of HCC patients and tumor-bearing rats. CF102 induced apoptosis and tumor growth inhibition. These data suggest A(3)AR as a novel targeted therapy to treat HCC.

Topics: Adenosine; Adenosine A3 Receptor Agonists; Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Liver Neoplasms; Male; Middle Aged; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A3; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Wnt Proteins