TNF-α and its inhibitors in cancer

Abstract

Tumor necrosis factor (TNF)-alpha is implicated in the same time in apoptosis and in cell proliferation. TNF-alpha 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-alpha functions have been intensively investigated. In this review we covered TNF-alpha, 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-alpha inhibitors, their pharmacokinetics, and their pharmacodynamics. Six TNF-alpha 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-alpha by these drugs has many side effects like malignancies 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.

Death-associated protein kinase 1 is an IRF3/7-interacting protein that is involved in the cellular antiviral immune response

“…30 Recent studies have also shown that DAPK1 is involved in a diverse range of signaling pathways and that it functions as a tumor suppressor. [31][32][33][34][35][36] However, whether and how DAPK1 is involved in virus-triggered type I IFN induction is unknown.…”

Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages

“…The complex interactions between the neoplastic and inflammatory cells, which are mediated by inflammatory cytokines, are essential features of the tumor microenvironment [14] . Tumor necrosis factor-a (TNF-a) is a proinflammatory cytokine predominantly produced by macrophages as well as tumor cells [15,16] , and is a cytokine ligand of the TNF family that interacts with different receptors of the TNF receptor superfamily. The activity of this system may be one of the drivers of progression in CRC [17] .…”

“…It has multiple effects on cell function by binding to specific high-affinity, cell-surface receptors. Apart from its apoptosis-inducing mechanisms, TNF-a may promote tumor growth at lower levels during cancer progression [15,16] . A mounting body of evidence has suggested that TNF-a mediates many critical processes of tumor progression, including oncogene activation, DNA damage, and tumor metastases [18,19] .…”

Tumor Necrosis Factor-αis Associated with Positive Lymph Node Status in Patients with Recurrence of Colorectal Cancer – Indications for Anti-TNF-αAgents in Cancer Treatment

“…TNF-α does not only act as pro-inflammatory cytokine contributing to the wide spectrum of human diseases including inflammatory diseases, but can also induce tumor development. Therefore, the use of TNF-α inhibitors with a focus in cancer treatment has been taken into account [54]. With regard to our results of increased TNF-α expression by cancer cells and its role in other diseases we hypothesize the inflammatory mechanism of action by this cytokine as an example for the seventh 'hallmark of cancer' in CRC.…”

“…TNF-α is produced by macrophages as well as tumor cells and has multiple effects on cell function by binding to specific, high-affinity cell surface receptors. Beside apoptotic mechanisms, TNF-α may even promote tumor growth at lower levels during cancer progression [54,55]. Interestingly, during cancer progression tumor cells from CRC have been described to lose their susceptibility for the induction of apoptosis [5].…”