Targeting death receptors to fight cancer: from biological rational to clinical implementation.
Considering that most currently available chemotherapeutic drugs work by inducing cell apoptosis, it is not surprising that many expectations in cancer research come from the therapeutic exploitation of the naturally occurring death pathways. Receptor mediated apoptosis depends upon the engagement of specific ligands with their respective membrane receptors and - within the frame of complex regulatory networks - modulates some key physiological and pathological processes such as lymphocyte survival, inflammation and infectious diseases. A pivotal observation was that some of these pathways may be over activated in cancer under particular circumstances, which opened the avenue for tumor-specific therapeutic interventions. Although one death-related ligand (e.g., tumor necrosis factor, TNF) is currently the basis of effective anticancer regimens in the clinical setting, the systemic toxicity is hampering its wide therapeutic exploitation. However, strategies to split the therapeutic from the toxic TNF activity are being devised. Furthermore, other death receptor pathways (e.g., Fas/FasL, TRAIL/TRAIL receptor) are being intensively investigated in order to therapeutically exploit their activity against cancer. This article summarizes the current knowledge on the molecular features of death receptor pathways that make them an attractive target for anticancer therapeutics. In addition, the results so far obtained in the clinical oncology setting as well as the issues to be faced while interfering with these pathways for therapeutic purposes will be overviewed.
Mocellin
S
S
Department of Oncological and Surgical Sciences, University of Padova, Italy. simone.mocellin@unipd.it
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053218:Receptors, Death Domain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha