Mini-reviewTargeting apoptosis pathways in lung cancer
Section snippets
Lung cancer
Lung cancer is the leading cause of cancer related deaths worldwide. It has been estimated that more than 1 million people die with it annually and approximately 1.4 millions are diagnosed per year, 12% of which are new cases [1]. Lung cancers are divided into small cell lung cancer (SCLC) which comprises of 15–20% of total lung cancer cases and remaining 80–85% are attributed to the non-small cell lung cancers (NSCLC). On the basis of histological characteristics NSCLC is further divided into
Apoptotic cell death
Apoptosis or programmed cell death is a physiological process that provides an effective, non-inflammatory way to remove redundant or damaged cells from tissues thereby securing tissue homeostasis [7]. Inhibition of apoptosis is considered as an essential step in tumorigenesis and is one of the hallmarks of cancer, allowing the survival of cells that accumulate oncogenic events that otherwise would have been removed by apoptosis [8]. A multitude of signals activated by variable triggers, such
Apoptosis as target for therapy
Standard cancer therapies such as chemotherapy and radiation eradicate tumor cells at least in part by indirectly activating the apoptotic machinery [17]. In this process the tumor suppressor p53 is an important effector that predominantly induces transcription-dependent mechanisms of apoptosis by upregulating pro-apoptotic genes such as PUMA, BAX and death receptors and subsequent activation of intrinsic and/or extrinsic apoptosis [18]. It is observed that around 50% of all types of lung
TRAIL receptor targeted therapy
Targeting of the TRAIL receptor signaling pathway is an attractive approach since it provides a direct apoptosis trigger that selectively kills tumor cells without harming normal cells [20]. Two membrane receptors mediate apoptosis, designated TRAIL-R1 (DR4) and TRAIL-R2 (DR5), whereas TRAIL-R3 (DcR1), -R4 (DcR2) and circulating osteoprotegerin (OPG) are non-functional decoy receptors that are able to sequester TRAIL causing suppression of apoptosis [21]. The mechanisms underlying the selective
BCL-2 targeted therapy
BCL-2 is frequently overexpressed in tumors and in lung cancer a meta-analysis has reported 76% and 35% in SCLC and NSCLC, respectively, of patients samples positive for BCL-2 [38]. Overexpression of anti-apoptotic BCL-2 family members is known to cause apoptosis and therapy resistance in a wide range of tumors and the development of therapies that target these apoptosis modulators appears to be a promising approach [39], [40]. Two main strategies to target BCL-2 and related family members are
Targeting the IAP family
The IAP family comprises a group of eighth structurally related proteins that share the presence of one or three zinc-binding motifs named the baculovirus IAP repeat (BIR) domain [65]. They constitute a functionally heterogeneous family and two members of the family, XIAP and survivin, are particularly involved in the inhibition of apoptosis. XIAP has three BIR domains that can interact and interfere with caspases-9, -3, and -7 activity. The BIR3 domain is involved in caspase-9 inhibition and
Apoptosis targeting strategies in clinical studies
Based on the promising preclinical results a number of therapeutic strategies that target the extrinsic or intrinsic pathway of apoptosis are being explored in early clinical studies in lung cancer. Agents that are most likely to produce approved products in the near future are TRAIL receptor targeted agents in NSCLC, antagonising inhibitors of XIAP or survivin and inhibition of the BCL-2 family of proteins both in NSCLC and SCLC (see Fig. 1). A summary of ongoing and completed clinical studies
Conclusions and future perspectives
Apoptosis targeting agents have shown promising anti-tumor activity in preclinical lung cancer models. Some of the agents appear to be particularly effective in either NSCLC or SCLC. For example, TRAIL receptor targeted agents are only tested in NSCLC patients, since DISC formation in SCLC is generally impaired. On the other hand, BCL-2 targeting agents as monotherapy display preferential activity for SCLC. The apoptotic drugs seem to be promising especially in combination with traditional
Conflict of interest
Milind M. Pore, T. Jeroen Hiltermann and Frank A.E. Kruyt have nothing to disclose.
Acknowledgements
FAEK is supported by the Dutch Cancer Society KWF-NK Grant 2006-3567 and Project T3-112 of the Dutch Top Institute Pharma.
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