Review
Targeted induction of apoptosis for cancer therapy: current progress and prospects

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Important breakthroughs in cancer therapy include clinical application of antibodies, such as Rituximab, and small inhibitory molecules, such as Iressa and Velcade. In addition, recent reports have indicated the therapeutic potential of physiological pro-apoptotic proteins such as TRAIL and galectin-1. Although unrelated at first glance, each strategy relies on the deliberate and selective induction of apoptosis in malignant cells. Importantly, therapy-resistance in cancer is frequently associated with de-regulation in the mechanisms that control apoptosis. However, cancer cells are often reliant on these molecular aberrations for survival. Therefore, selective induction of apoptosis in cancer cells but not normal cells seems feasible. Here, we review recent progress and prospects of selected novel anti-cancer approaches that specifically target and sensitize cancer cells to apoptosis.

Section snippets

Selective activation of apoptosis in cancer cells

Apoptosis is an elaborate cellular homeostasis mechanism that ensures correct development and function of multi-cellular organisms. In this respect, the immune system is perfectly equipped to target apoptosis selectively towards cells with potentially dangerous phenotypes. The immune system uses an enormous repertoire of highly selective receptors (e.g. on T and B cells) combined with various potent pro-apoptotic effector mechanisms [e.g. granzymes and fibroblast-associated cell surface (FAS)

Molecular pathways of apoptosis and cancer-specific defects

Central to the execution of apoptosis is the coordinated activation of a subset of caspases – executioner caspases – that cleave multiple cellular substrates, ultimately resulting in apoptotic cell death (Figure 1). These executioner caspases (caspase-3, caspase-6 and caspase-7) are themselves activated by so-called initiator caspases. All caspases are produced as inactive pro-enzymes and are activated by proteolytic processing.

In most physiological situations, apoptosis is initiated via the

Targeted induction of apoptosis using antibodies

Compared with their normal counterparts, cancer cells often display a qualitatively and/or quantitatively different repertoire of cell-surface molecules that can be selectively targeted in cancer therapy. Most-established strategies for targeted therapy are based on cancer-cell-selective monoclonal antibodies (MAbs). Often, the tumoricidal effect of antibody-based therapy relies on highly toxic and pro-apoptotic compounds directly conjugated to antibodies that potently activate apoptosis upon

Apoptosis by activation of members of the tumor necrosis factor (TNF) receptor family

The direct activation of the apoptotic machinery in cancer cells using recombinant soluble forms of tumor necrosis factor (TNF), FASL and TNF-related apoptosis-inducing ligand (TRAIL) has attracted much attention. TNF, FASL and TRAIL, which are three major immune effector molecules, all possess high tumoricidal pro-apoptotic activity.

However, severe cardiovascular toxicity has limited the therapeutic use of soluble TNF (sTNF) to loco-regional applications, such as isolated limb perfusion, where

Activation of apoptosis by modulating galectins

Recently, the physiologically occurring anti-proliferative galectins were shown to have promising anti-tumor activity [33]. Galectins are a family of lectins with affinity for β-galactoside residues of cell-surface glycoproteins expressed by both normal and cancer cells. However, upon binding, regulatory functions to which normal and cancer cells respond differently are enforced. For example, galectin-1 blocks the cell cycle in late S-phase by altering the expression of cell-cycle controller

Apoptosis by proteasome inhibition

Protein homeostasis is pivotal to cell survival and is mainly regulated by the ubiquitin–proteasome pathway (UPP) [39], which controls the half-life of the majority of cellular proteins. Inhibition of the UPP in cancer cells has yielded promising results. This has been highlighted by the recent approval of the proteasome inhibitor bortezomib (Velcade) for the treatment of multiple myeloma [40]. An important feature of bortezomib is the differential response of normal and cancer cells [41], the

Apoptosis by restoring p53 activity

The tumor-suppressor p53 is instrumental in the cellular response to stress signals and is crucial in the prevention of tumor development and the success of various anti-cancer strategies [56]. Over 50% of tumors possess inactivating mutations in p53, whereas in tumors that retain wild-type p53 its function is often impaired as a result of overexpression of the negative regulator human double minute-2 (HDM-2). HDM-2 binds to p53 and, consequently, p53 is subject to rapid proteasomal

Apoptosis by DNA-methylase inhibitors

DNA methylation has a regulatory role in gene expression during normal development but can also mediate epigenetic silencing of genes in cancer [64]. Many individual genes including tumor suppressors have been shown to undergo de novo methylation in specific tumor types. Specific DNA methyltransferases methylate DNA at the carbon-5 position of cytosine. An important example is the methylation of the E-cadherin promoter, which has an essential role in metastasis and invasiveness of breast cancer

Conclusions and perspectives

Targeted therapies that are designed to induce apoptosis in cancer cells selectively are currently the most promising anti-cancer strategies. These strategies aim to target and kill specifically tumor cells with no or minimal collateral damage. However, a fundamental problem is still that ‘primitive’ targeting is often simply not specific enough to enable the delivery of highly toxic agents. Therefore, the problem of cancer selectivity remains an important issue 76, 77, 78. As a consequence,

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