LETTER
JOP. J Pancreas (Online) 2010 Jul 5; 11(4):403-404.
Novel Drug Targets Based on Association between Inflammation and Pancreatic Ductal Adenocarcinoma
Muhammad Wasif Saif
Yale University School of Medicine. New Haven, CT, USA
Dear Sir,
We read with great interest the editorial published by Uomo et al. in the 2010 May issue of JOP. J Pancreas (Online) titled: "Inflammation and Pancreatic Ductal Adenocarcinoma: A Potential Scenario for Novel Drug Targets" [1]. There is a growing amount of evidence that inflammation plays a contributory role in the pathogenesis of cancer, including pancreatic carcinogenesis. Inflammatory states are characterized by the formation of reactive oxygen species and the induction of cell cycling for tissue growth and repair [1, 2, 3]. The initiation, promotion and expansion of tumors may be influenced by numerous components that also function in the inflammatory response. Recognized risk factors for pancreatic cancer include cigarette smoking, chronic/hereditary pancreatitis, obesity and type II diabetes. Each risk factor is linked by the fact that the inflammatory state significantly drives its pathology.
We agree with the authors that multiple links between inflammation and pancreatic adenocarcinoma has led to development of novel targeted therapy which is under evaluation both in vivo and in vitro studies to fight against pancreatic adenocarcinoma. Pancreatic cancer is one of the leading causes of cancer mortality in the United States. Current therapy for pancreatic cancer involves surgery, chemotherapy, and radiation therapy; however, the 5-year survival rate remains less than 5%. Therefore, developments of novel agents, in particular based on the pathogenesis of pancreatic adenocarcinoma are urgently indicated.
Nuclear Factor Kappa B (NF-kappa B) Activity
Few agents affecting NF-kappa B activity includes: MG132, a proteasome inhibitor [4], thymoquinone [5], fisetin, a natural flavonoid [6], sulforaphane [7], lidamycin [8], curcumin [9] and PHY906, a Chinese botanical formulation [10]. Of note characterization of sonic hedgehog as a novel NF-kappa B target gene that promotes NF-kappa B-mediated apoptosis resistance and tumor growth is potentially very important [11].
Reactive Oxygen Species (ROS)
Studies have been conducted recently on the protective effect of lycopene on oxidative stress-induced cell death of pancreatic acinar cells [12] and ascorbate-induced cytotoxicity in pancreatic cancer [13].
Proliferator-Activated Receptor-Gamma (PPAR-gamma)
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor that has been implicated in carcinogenesis and progression of various solid tumors, including pancreatic carcinoma [14]. The anti-tumour activity of the novel thiazolidinedione class PPAR-gamma agonist CS-7017 has recently been investigated [15]. CS-7017 inhibited the proliferation of pancreatic tumour cell line AsPC-1 in vitro at concentrations as low as 10 nmol/L. An elevation in the levels of adiponectin, a surrogate marker for PPAR-gamma activation was also observed in such studies [15]. These preclinical results support the evaluation of CS-7017 in a clinical trial.
Cyclooxygenase-2 (COX-2)
Several types of human tumors overexpress COX-2 but not COX-1. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis. Therefore, selective COX-2 inhibitors can reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. Nonselective NSAIDs such as sulindac and indomethacin inhibit not only COX-2 but COX-1, a cytoprtotective [16]. Consequently, nonselective NSAIDs can cause gastrointestinal ulceration, platelet dysfunction, and nephropathy [16]. For these reasons, selective inhibition of COX-2 such as meloxicam, celecoxib, and rofecoxib are preferable to treat neoplastic proliferation [17]. Such agents have been evaluated in the management of pancreatic cancer in combination with radiation therapy [18] as well as with systemic chemotherapy [19, 20].
Cytokines
Cytokines, in particular tumor necrosis factor-alpha (TNF-alpha), represent an important target for a novel therapeutic target to treat pancreatic adenocarcinoma. TNFerade is an adenovector, or DNA carrier, which contains the gene for TNF-alpha, an immune system protein with potent and well-documented anti-cancer effects, for direct injection into tumors. After administration, TNFerade stimulates the production of TNF-alpha in the tumor. Clinical studies have been evaluating TNFerade for use in combination with radiation and/or chemotherapy for the treatment of pancreatic cancers [21, 22, 23].
Considering the relative chemotherapy-resistance of pancreatic adenocarcinoma to classic cytotoxic agents used alone or in multi-modality combination, efforts to evaluate both old and new drugs directed at the inflammatory mechanisms is warranted to improve the overall prognosis for patients with pancreatic adenocarcinoma.
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Received May 15th, 2010 - Accepted May 18th, 2010
Key words celecoxib; Cell Proliferation; Cyclooxygenase 2; Cytokines; NF-kappa B; Pancreatic Neoplasms; Pancreatitis, Chronic; PPAR gamma; Reactive Oxygen Species
Abbreviations PPAR: proliferator-activated receptor-gamma
Conflict of interest The author has no potential conflict of interest
Correspondence
Muhammad
Wasif Saif
Yale University School of Medicine
333 Cedar Street, FMP 116
New Haven, CT
USA
Phone: +1-203.737.1600
Fax: +1-203.785.3788
E-mail: wasif.saif@yale.edu
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