Trends in Molecular Medicine
ReviewTargeted induction of apoptosis for cancer therapy: current progress and prospects
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,
References (80)
- et al.
Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases
Curr. Opin. Cell Biol.
(2004) - et al.
The importance of p53 location: nuclear or cytoplasmic zip code?
Drug Resist. Updat.
(2003) Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity
Cancer Cell
(2004)Antibody-targeted chemotherapy of acute myeloid leukemia using gemtuzumab ozogamicin (Mylotarg)
Blood Cells Mol. Dis.
(2003)Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies
Blood
(2004)The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction
Blood
(2002)Hu1D10 induces apoptosis concurrent with activation of the AKT survival pathway in human chronic lymphocytic leukemia cells
Blood
(2004)Current uses of isolated limb perfusion in the clinic and a model system for new strategies
Lancet Oncol.
(2003)A Fas agonist induces high levels of apoptosis in haematological malignancies
Leuk. Res.
(2006)The tumor necrosis factor-related apoptosis-inducing ligand receptors TRAIL-R1 and TRAIL-R2 have distinct cross-linking requirements for initiation of apoptosis and are non-redundant in JNK activation
J. Biol. Chem.
(2000)
Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling
J. Biol. Chem.
Simultaneous inhibition of epidermal growth factor receptor (EGFR) signaling and enhanced activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis induction by an scFv:sTRAIL fusion protein with specificity for human EGFR
J. Biol. Chem.
Generation of a FasL-based proapoptotic fusion protein devoid of systemic toxicity due to cell-surface antigen-restricted activation
J. Biol. Chem.
Exceptionally potent anti-tumor bystander activity of an scFv:sTRAIL fusion protein with specificity for EGP2 toward target antigen-negative tumor cells
Neoplasia
6 A phase I and pharmacokinetic (PK) study of an agonistic, fully human monoclonal antibody, HGS-ETR2, to the TNFα-related apoptosis inducing ligand receptor 2 (TRAIL-R2) in patients with advanced cancer
Eur. J. Cancer Suppl.
Turning cell cycle controller genes into cancer drugs: A role for an antiproliferative cytokine (βGBP)
Biochem. Pharmacol.
Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection: a potential mechanism of tumor-immune privilege
Cancer Cell
ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia
Blood
TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90
Mol. Cell
Antileukemia activity of the combination of 5-aza-2′-deoxycytidine with valproic acid
Leuk. Res.
Overcoming limitations of natural anticancer drugs by combining with artificial agents
Trends Pharmacol. Sci.
Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL
Cell
Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice
Cancer Res.
Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy
Cancer Res.
Phase I trial of recombinant immunotoxin RFB4(dsFv)–PE38 (BL22) in patients with B-cell malignancies
J. Clin. Oncol.
Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention
Oncogene
Three new prodrugs for suicide gene therapy using carboxypeptidase G2 elicit bystander efficacy in two xenograft models
Cancer Res.
Gap junction-mediated bystander effect in primary cultures of human malignant gliomas with recombinant expression of the HSVtk gene
Exp. Cell Res.
Fas receptor-mediated apoptosis: a clinical application?
J. Pathol.
Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety
J. Pharmacol. Exp. Ther.
TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies
Cancer Res.
Differential activation of TRAIL-R1 and -2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative
Oncogene
Target cell-restricted and -enhanced apoptosis induction by a scFv:sTRAIL fusion protein with specificity for the pancarcinoma-associated antigen EGP2
Int. J. Cancer
Target cell-restricted apoptosis induction of acute leukemic T cells by a recombinant tumor necrosis factor-related apoptosis-inducing ligand fusion protein with specificity for human CD7
Cancer Res.
CD7-restricted activation of Fas-mediated apoptosis: a novel therapeutic approach for acute T-cell leukemia
Blood
Phase I study of a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis inducing ligand death receptor 4 (TRAIL-R1) in subjects with advanced solid malignacies or non-Hodgkin's lyphoma (NHL)
J. Clin. Oncol.
Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy
J. Exp. Med.
Acquired resistance to TRAIL-induced apoptosis in human ovarian cancer cells is conferred by increased turnover of mature caspase-3
Mol. Cancer Ther.
Contribution of epigenetic silencing of tumor necrosis factor-related apoptosis inducing ligand receptor 1 (DR4) to TRAIL resistance and ovarian cancer
Mol. Cancer Res.
Galectins as modulators of tumour progression
Nat. Rev. Cancer
Cited by (115)
In vivo and in vitro apoptosis induced by new acaricidal ethyl-carbamates in Rhipicephalus microplus
2021, Ticks and Tick-borne DiseasesWater mediated procedure for preparation of stereoselective oximes as inhibitors of MRCK kinase
2020, Journal of Molecular StructurePhytochemical constituents and anticancer activities of Tarchonanthus camphoratus essential oils grown in Saudi Arabia
2020, Saudi Pharmaceutical JournalSynthesis, characterization, DNA/BSA interactions and in vitro cytotoxicity study of palladium(II) complexes of hispolon derivatives
2020, Journal of Inorganic BiochemistryIdentification of a dual inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) pathways
2015, Journal of Biological Chemistry