Send Orders for Reprints to reprints@benthamscience.net Recent Patents on Biomarkers 2013, 3, 65-71 65 Functional Evaluation of Imatinib Mesylate in Hepatocellular Carcinoma Cells Mai A. Saad Zaghloul 1 , Ashraf H. Abadi 2 and Ahmed I. Abdelaziz 1, * 1 The Molecular Pathology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt; 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt Received: August 29, 2012; Accepted: November 5, 2012; Revised: November 06, 2012 Abstract: Hepatocellular Carcinoma remains a major fatal disease that is resistant to most cytotoxic therapeutics owed to the aberrant activation of signalling cascades. Recent patents reveal a new family of drugs that has been studied for molecularly targeting these cascades; multi-kinase inhibitors, are nowadays considered as novel therapeutic approaches. Therefore in this study, we aimed at investigating the impact of Imatinib mesylate, a tyrosine kinase inhibitor, on Human Hepatoma (HuH-7) cellular behavior and specifically its effect on p53 tumor suppressor gene. HuH-7 cells were trans- fected with a reporter vector containing a specific enhancer element that is activated upon binding to intracellular p53; consequently downstream luciferase reporter gene is activated. Cells were treated with Imatinib and we looked for p53 in- duction upon drug stimulation. Additionally; viability, metabolism, proliferation and apoptosis were evaluated. Upon Imatinib treatment, p53 expression showed a significant increase represented in increased luminescence. Moreover; a de- crease in cellular viability and metabolic activity along with a considerable inhibition of proliferation and a vast increase in Caspase 9 activity were observed when compared to untreated cells. This study suggests that the effects of Imatinib mesylate might be attributable to enhanced active p53 in HuH-7 cells with consequent reduction in cancer progression properties. The article also summarizes some recent relevant patents. Keywords: Hepatocellular carcinoma, HuH-7, imatinib mesylate, luciferase reporter gene, molecular targeted therapy, p53. INTRODUCTION Hepatocellular carcinoma (HCC) is one of the most ag- gressive cancers worldwide; where over 600,000 deaths oc- cur annually due to this disease [1]. Although several HCC treatments are available, yet they are restricted to the stage at which the cancer is diagnosed. The majority of HCC patients are usually diagnosed at a very late stage which makes the potentially curative therapy the least effective. While most of the early diagnosed patients are limited to either liver trans- plant or resection and only 10-15% are suitable candidates for medical treatments to which they become resistant shortly after [2]. HCC is considered a heterogeneous tumor with several genomic alterations causing aberrant activation of signaling pathways such as Ras/Raf/Mek [3], PI3k/Akt [4], and in addition to several signaling molecules such as p53 tumor suppressor protein, consequently halting its func- tion in inhibiting proliferation and inducing apoptosis [5]. This creates a research challenge to fulfil an urging need for new therapeutic strategies that could be curative for the ma- jority of patients with this aggressive disease. A recently emerging class of therapeutics is now focusing on targeting specific signaling molecules contributing to the pathogenesis *Address correspondence to this author at the Molecular Pathology Re- search Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, The German University in Cairo (GUC), New Cairo City - Main Entrance Al Tagamoa Al Khames 11835, Cairo, Egypt; Tel: +20-2-27590714; Fax: +20-2-27581041; E-mail: ahmed.abdel-aziz@guc.edu.eg of HCC tumors in an attempt to reverse the progress of the disease and diminish the resistance to therapy; one example is the multi-kinase inhibitors. Sorafenib tosylate (Nexavar ® tablets, Bayer Pharmaceuticals Corp.), a small molecule Raf kinase inhibitor and Vascular Endothelial Growth Factor (VEGF) receptor kinase inhibitor, has been approved in 2007 by the Food and Drug Administration (FDA) for the treat- ment of patients with unresectable hepatocellular carcinoma (HCC) as the first systemic therapeutic approach [6]. Soraf- enib has shown to increase overall survival and time to pro- gression in advanced unresectable HCC patients [7] and de- crease the development of post surgical intrahepatic recur- rences and abdominal metastasis in mice models [8]. Al- though the direct action of Sorafenib on p53 is not eluci- dated, it has been reported that its action on Mitogen- activated Protein Kinase (MAPK) signaling is differential according to the status of p53 [9]. Additionally, Imatinibmesylate (STI-571; Gleevec ® tab- lets, Novartis Pharmaceuticals Corp.); a tyrosine kinase in- hibitor, targets specifically bcr/abl [10], PDGF-R [11] and c- kit [12], is indicated for the treatment of Philadelphia chro- mosome-positive (Ph+) Chronic Myelogeneous Leukemia (CML) [10] and is approved by the FDA early 2012 as an adjuvant treatment for Gastrointestinal Stromal Tumors (GIST) [13]. However, due to the presence of abrupt muta- tions and therefore abnormally controlled signaling path- ways, resistance to therapy is recurrent. In a recent patency, new means were invented to circumvent the resistance to Imatinib treatment due to Kit mutation in Gastrointestinal 2210-3104/13 $100.00+.00 © 2013 Bentham Science Publishers