ORIGINAL PAPER TNF-a and its inhibitors in cancer Ine`s Zidi Souhir Mestiri Aghleb Bartegi Nidhal Ben Amor Received: 8 January 2009 / Accepted: 17 February 2009 / Published online: 11 March 2009 Ó Humana Press Inc. 2009 Abstract Tumor necrosis factor (TNF)-a is implicated in the same time in apoptosis and in cell proliferation. TNF-a not only acts as pro-inflammatory cytokine conducing to wide spectrum of human diseases including inflammatory diseases, but can also induce tumor development. The molecular mechanisms of TNF-a functions have been intensively investigated. In this review we covered TNF-a, the molecule, its signaling pathway, and its therapeutic functions. We provide a particular insight in its paradoxical role in tumor promotion and in its use as anti-tumor agent. This review considers also the recent findings regarding TNF-a inhibitors, their pharmacokinetics, and their phar- macodynamics. Six TNF-a inhibitors have been considered here: Infliximab, Adalimumab, Golimumab, CDP870, CDP571, Etanercept, and Thalidomide. We discussed the clinical relevance of their functions in treatment of several diseases such as advanced inflammatory rheumatic and bowel disease, with a focus in cancer treatment. Targeting TNF-a by these drugs has many side effects like malig- nancies development, and the long-term sequels are not very well explored. Their efficacy and their safety were discussed, underscoring the necessity of close patients monitoring and of their caution use. Keywords TNF-a Á Anti-TNF-a Á Inhibitors Á Cancer Á Therapy Introduction It is now almost over 30 years since the isolation of tumor necrosis factor (TNF)-alpha (TNF-a)[1]. This discovery had an incredible insight into control of the immune sys- tem. It is now clear that TNF-a not only is a pro- inflammatory cytokine but it is also known that TNF-a is a major mediator of inflammatory diseases such as Crohn’s disease (CD) and rheumatoid arthritis (RA) [2]. It is also implicated in apoptosis and cell survival [3]. This review will emphasize the relations between TNF-a and its inhibitors, and cancer and its therapy. We will appreciate the impact of therapeutic use of TNF-a and its inhibitors in the cancer development. This review high- lights recent in vitro studies and clinical trials related to TNF-a blockade. First, the molecular mechanism of TNF-a signaling will be briefly reviewed. TNF-a, receptors, and signaling pathways TNF-a gene is localized on the human chromosome 6 (6p21.3). It is a 17-KDa protein initially expressed as a transmembrane precursor (pro-TNF-a, 26 KDa) that will be cleaved at the cell surface by specific processing pro- tease called TACE (TNF-converting enzyme), also known as ADAM17 (a disintegrin and metalloproteinase17) [4]. This pro-inflammatory cytokine can be produced by diverse kind of cells comprising immune cells, such as activated T cells, activated monocytes, and macrophages, and other cells such as Langerhans cells, keratinocytes, fibroblasts, and astrocytes. Two receptors for TNF-a, in its soluble or membrane form, are identified: TNFR1 (also called p55 or CD120a) and TNFR2 (also called p75 or CD120b) [5, 6]. TNFR1 is I. Zidi (&) Á S. Mestiri Á A. Bartegi Á N. B. Amor Laboratory of Biochemistry, Research Unit 02/UR/09-01, High Institute of Biotechnology (Institut Supe´rieur de Biotechnologie), BP 74, Avenue Tahar Haddad, Monastir 5000, Tunisia e-mail: ines.zidi@techemail.com Med Oncol (2010) 27:185–198 DOI 10.1007/s12032-009-9190-3