Preface [Hot Topic: Anticancer Agents: To Kill in a Good Cause (Guest Editor : Eric Solary)].

Anticancer agents are used to kill tumour cells with collateral damage as limited as possible. One of the cell death triggered by these agents is apoptosis, an orderly and synchronised process that involves a mitochondrial-dependent, Bcl-2 regulated pathway ending with caspase activation. In this issue of Current Medical Chemistry - Anticancer Agents, five different aspects of tumour cell apoptosis triggered by chemotherapeutic drugs are reviewed.Simone Fulda and Klaus-Michael Debatin explore the contribution of death receptor signalling in cancer therapy. A number of studies support the assertion that anticancer agents induce the formation of a plasma membrane-associated, death inducing signalling complex involving CD95, FADD and caspase-8. Activation of caspase-8 in this complex may contribute to druginduced cell death and negative regulators of this pathway, including caspase-8 down-regulation and overexpression of IAPs (Inhibitor of Apoptosis Proteins) or FLIP contribute to drug resistance at the cellular level. In addition, anticancer drugs sensitise tumour cells to death induced by engagement of death receptors such as CD95, DR4 and DR5, which suggests that death receptor agonists could be used in combination with common anticancer drugs to improve their efficacy. The DR4- and DR5-ligand known as TRAIL (Tumor necrosis factor-Related Apoptosis-Inducing Ligand), whose toxicity is limited in preclinical studies, may be a good candidate for such a combination.Christine Bezombes et al analyse the role of raft microdomains in death response to DNA damaging agents such as cytarabine and daunorubicin. A ceramide-mediated pathway is initiated by these agents through the activation of a sphingomyelinase that hydrolyses sphingomyelin to produce ceramide. This pathway leads to a protein kinase cascade that contributes to apoptosis. The spatio-temporal organisation of sphingomyelinase activation is discussed with a special attention to the role of lipid microdomains in the plasma membrane. Defects in rafts could contribute to cellular drug resistance and pharmacological manipulation of this lipid / kinase pathway could increase cancer cell chemosensitivity.Olivier Sordet et al focus on connections between topoisomerase inhibitor-induced DNA damage and apoptotic pathways. These drugs generate cleavage complexes that are converted into DNA lesions during DNA replication and transcription. Sensor protein kinases such as DNA-PK (DNA-dependent protein kinase), ATM (Ataxia Telangiectasia Modified) and ATR (Ataxia Telangiectasia and Red 3-modified) bind to DNA breaks, then phosphorylate downstream substrates such a c-Abl and Chk2. The authors provide nice molecular interaction maps, demonstrating that the next challenge will be to elucidate how manipulation of these connected pathways will improve the efficacy of these anticancer agents.Another target for anticancer drugs is tubulin. Taxanes are commonly used antineoplastic agents that promote microtubule polymerisation and inhibit tubulin depolymerisation. Valérie Ganansia-Leymarie et al summarise the protein kinase signalling pathways activated by these anticancer drugs, leading to caspase-dependent apoptotic cell death. Bcl-2 has been shown to be phosphorylated at serine residues between BH3 and BH4 regions by microtubule-targeting drugs and this phosphorylation was suggested to contribute either to cell death or cell cycle arrest.Proteins of the Bcl-2 family are key regulators of apoptosis. Whether they act at the mitochondrial level by preventing the release of soluble molecules or upstream of these mitochondrial events is currently a controversial issue. Whatever the exact answer to this question, anti-apoptotic proteins of the Bcl-2 family are attractive targets for a chemosensitising strategy. Current strategies to target Bcl-2 proteins are explored by Ali Bettaïeb et al who analyse the current clinical results obtained with an antisense oligonucleotide strategy and report that alternative approaches are currently developed. Altogether, these papers summarise a large piece of data demonstrating that understanding of cell death mechanisms has opened numerous opportunities to improve the clinical use of classical anticancer agents.