Abstract
The avoidance of apoptosis is one of the hallmarks of cancer cells. In addition, failure to induce apoptosis by anticancer agents, either due to limitations of the drug or the tumour cell evading apoptosis, is a reason for chemotherapeutic failure. Two general pathways for apoptotic cell death have been characterised, the extrinsic and intrinsic pathways which merge in the final common pathway. X-linked inhibitor of apoptosis protein (XIAP) is an anti-apoptotic protein in the final common pathway that inhibits caspases and suppresses apoptosis. XIAP is over-expressed in many cancer cell lines and cancer tissues. High XIAP expression has been correlated with resistance to chemotherapy and radiotherapy and to poor clinical outcome by some investigators. Manipulation of apoptosis is an attractive therapeutic concept. Much effort has been spent on inhibiting the anti-apoptotic protein, B cell lymphoma gene 2 (Bcl-2) which is part of the intrinsic pathway. Now attention is turning to inhibition of XIAP as a cancer drug target. It has been argued that it is more effective to block the final common pathway rather than just the intrinsic arm. Inhibition of XIAP can be with either antisense oligonucleotides (ASO) or small molecule inhibitors. In vitro, XIAP antagonists produce XIAP knockdown and apoptosis which is associated with sensitisation of tumour cells to radiotherapy and cytotoxic drugs. In vivo, XIAP antagonists have antitumour effects and sensitise tumours to the effects of chemotherapy. This review will summarise the preclinical data for both ASO and small molecule inhibition of XIAP and discuss emerging Phase I data. Future strategies for manipulation of XIAP and the clinical development of XIAP inhibitors will be discussed.
Keywords: XIAP, apoptosis, anticancer therapy
Current Cancer Drug Targets
Title: IAPs as a Target for Anticancer Therapy
Volume: 7 Issue: 8
Author(s): S. Danson, E. Dean, C. Dive and M. Ranson
Affiliation:
Keywords: XIAP, apoptosis, anticancer therapy
Abstract: The avoidance of apoptosis is one of the hallmarks of cancer cells. In addition, failure to induce apoptosis by anticancer agents, either due to limitations of the drug or the tumour cell evading apoptosis, is a reason for chemotherapeutic failure. Two general pathways for apoptotic cell death have been characterised, the extrinsic and intrinsic pathways which merge in the final common pathway. X-linked inhibitor of apoptosis protein (XIAP) is an anti-apoptotic protein in the final common pathway that inhibits caspases and suppresses apoptosis. XIAP is over-expressed in many cancer cell lines and cancer tissues. High XIAP expression has been correlated with resistance to chemotherapy and radiotherapy and to poor clinical outcome by some investigators. Manipulation of apoptosis is an attractive therapeutic concept. Much effort has been spent on inhibiting the anti-apoptotic protein, B cell lymphoma gene 2 (Bcl-2) which is part of the intrinsic pathway. Now attention is turning to inhibition of XIAP as a cancer drug target. It has been argued that it is more effective to block the final common pathway rather than just the intrinsic arm. Inhibition of XIAP can be with either antisense oligonucleotides (ASO) or small molecule inhibitors. In vitro, XIAP antagonists produce XIAP knockdown and apoptosis which is associated with sensitisation of tumour cells to radiotherapy and cytotoxic drugs. In vivo, XIAP antagonists have antitumour effects and sensitise tumours to the effects of chemotherapy. This review will summarise the preclinical data for both ASO and small molecule inhibition of XIAP and discuss emerging Phase I data. Future strategies for manipulation of XIAP and the clinical development of XIAP inhibitors will be discussed.
Export Options
About this article
Cite this article as:
Danson S., Dean E., Dive C. and Ranson M., IAPs as a Target for Anticancer Therapy, Current Cancer Drug Targets 2007; 7 (8) . https://dx.doi.org/10.2174/156800907783220471
DOI https://dx.doi.org/10.2174/156800907783220471 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Paving Roads for New Drugs in Oncology
Recent Patents on Anti-Cancer Drug Discovery Subject Index To Volume 5
Anti-Infective Agents in Medicinal Chemistry Persistent Clinical Response of Infliximab Therapy in Patients with Refractory Rheumatoid Arthritis, over a 3-Year Period
Current Clinical Pharmacology Cryopreservation of Ovarian Tissue: State of the Art in 2007
Current Women`s Health Reviews Treatment for Cancer Patients with Oral Mucositis: Assessment Based on the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer in International Society of Oral Oncology (MASCC/ISOO) in 2013 and Proposal of Possible Novel Treatment with a Japanese Herbal Medicine
Current Pharmaceutical Design Bioengineering RNA Silencing Across the Life Kingdoms
Recent Patents on Biotechnology Protocatechuic Acid and Human Disease Prevention: Biological Activities and Molecular Mechanisms
Current Medicinal Chemistry New Strategies for Therapeutic Cancer Vaccines
Anti-Cancer Agents in Medicinal Chemistry Paraneoplastic Pemphigus: Autoimmune-Cancer Nexus in the Skin
Anti-Cancer Agents in Medicinal Chemistry Specific Targeting of Akt Kinase Isoforms: Taking the Precise Path for Prevention and Treatment of Cancer
Current Drug Targets Chemosensitization of Prostate Cancer by Modulating Bcl-2 Family Proteins
Current Drug Targets The HIV-1 Tat Protein: A Multifaceted Target for Novel Therapeutic Opportunities
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Past, Present and Future Strategies of Immunotherapy in Gynecological Malignancies
Current Molecular Medicine Targeting the Mitochondrial Electron Transport Chain Complexes for the Induction of Apoptosis and Cancer Treatment
Current Pharmaceutical Biotechnology Flavonoid-Based Cancer Therapy: An Updated Review
Anti-Cancer Agents in Medicinal Chemistry Phosphorothioate Oligonucleotides: Effectiveness and Toxicity
Current Drug Targets Chelating Agents for Metal Intoxication
Current Medicinal Chemistry Dietary Supplement Therapies for Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis
Current Pharmaceutical Design T Cell Suicide Gene Therapy to Aid Haematopoietic Stem Cell Transplantation
Current Gene Therapy Effect of Visnagin on Altered Steroidogenesis and Spermatogenesis, and Testicular Injury Induced by the Heavy Metal Lead
Combinatorial Chemistry & High Throughput Screening