Inhibitor of Apoptosis (IAP) proteins as therapeutic targets for radiosensitization of human cancers

doi:10.1016/j.ctrv.2012.01.005

Cancer Treatment Reviews

Volume 38, Issue 6, October 2012, Pages 760-766

https://doi.org/10.1016/j.ctrv.2012.01.005 Get rights and content

Summary

Radiotherapy initiates a variety of signaling events in cancer cells that eventually lead to cell death in case the DNA damage cannot be repaired. However, the signal transduction pathways that mediate cell death in response to radiation-inflicted DNA damage are frequently disturbed in human cancers, contributing to radioresistance. For example, aberrant activation of antiapoptotic programs such as high expression of Inhibitor of Apoptosis (IAP) proteins has been shown to interfere with the efficacy of radiotherapy. Since IAP proteins have been linked to radioresistance in several malignancies, therapeutic targeting of IAP proteins may open new perspectives to overcome radioresistance. Therefore, molecular targeting of IAP proteins may provide novel opportunities to reactivate cell death pathways that mediate radiation-induced cytotoxicity. A number of strategies have been developed in recent years to antagonize IAP proteins for the treatment of cancers. Some of these approaches have already been translated into a clinical application. While IAP protein-targeting agents are currently being evaluated in early clinical trials alone or in combination with conventional chemotherapy, they have not yet been tested in combination with radiation therapy. Therefore, it is a timely subject to discuss the opportunities of antagonizing IAP proteins for radiosensitization. Preclinical studies demonstrating the potential of this concept in relevant in vitro and in vivo models underscore that this combination approach warrants further clinical investigation. Thus, combination protocols using IAP antagonists together with radiotherapy may pave the avenue to more effective radiation-based treatment options for cancer patients.

Introduction

The anticancer activity of most cytotoxic therapies which are currently used in the clinical management of cancer patients including radiotherapy is based on their ability to activate cell death programs such as apoptosis in cancer cells. Apoptosis or programmed cell death is an intrinsic program that is in place in every cell of the human body, including cancer cells.¹ A characteristic feature of human cancers is the inability to mount a proper apoptotic response during tumor progression or upon treatment with cytotoxic therapies.² Therefore, evasion of apoptosis constitutes a critical cause of primary or acquired treatment resistance that frequently occurs in various human cancers. This also applies to the resistance of cancers to radiotherapy, one of the main pillars of cancer therapy. Therefore, a better understanding of the molecular events that are responsible for the defects encountered in the apoptosis signaling network may offer novel perspectives to tackle treatment resistance, including radioresistance of human cancers. This review focuses on apoptosis resistance caused by aberrant expression and/or function of Inhibitor of Apoptosis (IAP) proteins, a family of antiapoptotic proteins, and discusses the opportunities of how the targeting of IAP proteins can be translated into the design of new radiation-based treatment protocols.

Section snippets

Signaling pathways in radiation-induced cell death

Radiation-induced signaling events can be initiated in distinct cellular compartments, for example the nucleus, the cytosol or the plasma membrane.³ In response to DNA damage that is sensed in the nucleus, the tumor suppressor and checkpoint protein p53 accumulates and becomes activated, thereby initiating cell cycle arrest, DNA repair and, in case of severe DNA damage, the induction of cell death.⁴ Furthermore, radiation can stimulate the production of reactive oxygen species (ROS) that can

Targeting IAP proteins for radiosensitization

On theoretical grounds, targeting IAP proteins may present a particularly promising approach to overcome radioresistance, since some IAP proteins such as XIAP and cIAP1 are among the proteins that can be regulated at the level of translation under cellular stress conditions.²¹ Accordingly, the messenger RNA (mRNA) molecules of XIAP and cIAP1 are translated via an internal ribosome entry site (IRES).22, 23 This IRES site allows continued translation of the protein even under cellular stress

Genetic interventions to target IAP proteins

To test the therapeutic potential of neutralizing IAP proteins to increase radiosensitivity of human cancers, a number of different genetic strategies have been employed (Table 1). For example, overexpression of Smac, the endogenous inhibitor of IAP proteins, has been reported to present a potent mean to increase radiation-induced cell death in a variety of human cancers, including neuroblastoma, glioblastoma, pancreatic and breast carcinoma.30, 31 Both the full-length and the mature forms of

Pharmacological interventions to target IAP proteins

In addition to genetic strategies to interfere with aberrant expression of IAP proteins in order to increase radiosensitivity of cancers, a number of pharmacological approaches have been developed to neutralize IAP proteins (Table 2). These efforts focused on the development of small molecule compounds that mimick the N-terminal stretch of the endogenous Smac protein. Small molecule IAP inhibitors were reported to sensitize pancreatic carcinoma cells for irradiation-induced apoptosis.³²

Molecular mechanisms

The following common picture has emerged so far from these preclinical studies into the underlying molecular mechanisms that mediate the cooperative induction of apoptosis by IAP antagonists and radiotherapy (Fig. 1). Neutralizing IAP proteins in conjunction with irradiation results in increased activation of the caspase cascade as well as enhanced mitochondrial outer membrane permeabilization involving increased loss of mitochondrial membrane potential and cytochrome c release from the

Clinical development of IAP protein-targeting agents

The concept to target IAP proteins for therapeutic purposes has been transferred into a clinical context in recent years. Both antisense oligonucleotides as well as small molecule inhibitors of IAP proteins have been evaluated in phase I/II clinical trials either as monotherapy or in combination with conventional chemotherapeutics (Table 3). In general, XIAP antisense oligonucleotides and IAP antagonists were well tolerated in these early clinical trials,56, 57, 58, 59, 60, 61 with the

Conclusions

IAP proteins are aberrantly expressed in various human cancers and represent promising molecular targets for therapeutic intervention in order to restore the ability of cancer cells to undergo cell death in response to radiotherapy. IAP protein-targeting agents have shown synergistic antitumor activity in combination with irradiation in a wide variety of preclinical models. Therefore, the concept to antagonize IAP proteins in order to increase radiosensitivity is considered as a promising

Conflict of interest

None to declare.

Acknowledgements

The expert secretarial assistance of C. Hugenberg is greatly appreciated. Work in the author’s laboratory is supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, the Bundesministerium für Forschung und Technologie, IAP6/18 and the European Community (ApopTrain, APO-SYS).

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New DrugsInhibitor of Apoptosis (IAP) proteins as therapeutic targets for radiosensitization of human cancers

Summary

Introduction

Section snippets

Signaling pathways in radiation-induced cell death

Targeting IAP proteins for radiosensitization

Genetic interventions to target IAP proteins

Pharmacological interventions to target IAP proteins

Molecular mechanisms

Clinical development of IAP protein-targeting agents

Conclusions

Conflict of interest

Acknowledgements

Cell death in health and disease

J Cell Mol Med

Tumor resistance to apoptosis

Int J Cancer

Signal transduction and cellular radiation responses

Radiat Res

DNA damage-induced cell death by apoptosis

Trends Mol Med

Oxidative stress and apoptosis: impact on cancer therapy

J Pharm Sci

Radiation and ceramide-induced apoptosis

Oncogene

The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction

Cell Death Differ

MAPK pathways in radiation responses

Oncogene

Ionizing radiation-induced, Bax-mediated cell death is dependent on activation of cysteine and serine proteases

Cell Growth Differ

Apoptosis: controlled demolition at the cellular level

Nat Rev Mol Cell Biol

Distinct stages of cytochrome c release from mitochondria: evidence for a feedback amplification loop linking caspase activation to mitochondrial dysfunction in genotoxic stress induced apoptosis

Cell Death Differ

Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy

Oncogene

Targeting the extrinsic apoptosis pathway in cancer

Cytokine Growth Factor Rev

Targeting mitochondria for cancer therapy

Nat Rev Drug Discov

Targeting IAP proteins for therapeutic intervention in cancer

Nat Rev Drug Disc

Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death

Nat Rev Mol Cell Biol

Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family

EMBO Rep

XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization

Mol Cell

Activation of NF-kappa B by XIAP, the X chromosome-linked inhibitor of apoptosis, in endothelial cells involves TAK1

J Biol Chem

(Un)expected roles of c-IAPs in apoptotic and NFkappaB signaling pathways

Cell Cycle

IRES in distress: translational regulation of the inhibitor of apoptosis proteins XIAP and HIAP2 during cell stress

Cell Death Differ

A new internal-ribosome-entry-site motif potentiates XIAP-mediated cytoprotection

Nat Cell Biol

The translation of an antiapoptotic protein HIAP2 is regulated by an upstream open reading frame

Cell Death Differ

Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death

Oncogene

Regulation of XIAP translation and induction by MDM2 following irradiation

Cancer Cell

AEG-35156, an antisense oligonucleotide against X-linked inhibitor of apoptosis for the potential treatment of cancer

Curr Opin Investig Drugs

IAP antagonists: promising candidates for cancer therapy

Drug Discov Today

Targeting IAPs as an approach to anti-cancer therapy

Curr Top Med Chem

Structural and biochemical basis of apoptotic activation by Smac/DIABLO

Nature

Sensitization for gamma-irradiation-induced apoptosis by second mitochondria-derived activator of caspase

Cancer Res

Smac/DIABLO enhances the therapeutic potential of chemotherapeutic drugs and irradiation, and sensitizes TRAIL-resistant breast cancer cells

Mol Cancer

Sensitization of pancreatic carcinoma cells for gamma-irradiation-induced apoptosis by XIAP inhibition

Oncogene

New Drugs
Inhibitor of Apoptosis (IAP) proteins as therapeutic targets for radiosensitization of human cancers