Abstract
The occurrence of chemoresistance is a serious problem in the treatment of cancer, urging the need for secondand third-line treatment options that rely on different cell death pathways to overcome previously acquired resistance mechanisms. The inhibition of proteasomal activity by specific proteasome inhibitors or cross-reactivity of certain protease inhibitors with proteasomal enzymes recently became of interest because of the anti-tumoral properties of these agents. We tested the proteasome inhibitor bortezomib and the HIV protease inhibitor nelfinavir on human cervical cancer cells. Both drugs induced cell cycle arrest in cervical cancer cells, as reflected by marked changes in the expression of cell cycle-regulatory cyclins and ensuing mitochondrial-independent apoptosis. Upregulation of the molecular chaperone BiP and the cell stress marker ATF3 indicated induction of the unfolded protein response (UPR) as the main cause of apoptosis induced by these drugs in cervical cancer cells. Unlike in leukemia cells, bortezomib mainly inhibited the caspase-like activity of the proteasome in cervical cancer cells. Nelfinavir exhibited no effects on proteasomal activity in cervical cancer cells and leukemia cells. Although both bortezomib and nelfinavir acted on cisplatin-resistant cervical cancer cells (SiHa), neither of the drugs induced a sensitization to cisplatin treatment. Instead, both drugs could effectively be combined with each other, and enhanced the efficacy of an apoptosis-inducing TRAIL receptor antibody. These results suggest that both bortezomib and nelfinavir are effective agents against chemoresistant cervical cancer cells and might be of interest for clinical studies on cervical cancer patients with recurrent or metastatic cancer.
Keywords: Apoptosis, bortezomib, cervical cancer, nelfinavir, proteasome, TRAIL, alkaline phosphatase, activating transcription factor, polyvinylidene fluoride, radio immunoprecipitation buffer, extracellular signal-regulated kinase
Current Cancer Drug Targets
Title: Bortezomib Targets the Caspase-Like Proteasome Activity in Cervical Cancer Cells, Triggering Apoptosis That Can be Enhanced by Nelfinavir
Volume: 11 Issue: 7
Author(s): A. Bruning, M. Vogel, I. Mylonas, K. Friese and A. Burges
Affiliation:
Keywords: Apoptosis, bortezomib, cervical cancer, nelfinavir, proteasome, TRAIL, alkaline phosphatase, activating transcription factor, polyvinylidene fluoride, radio immunoprecipitation buffer, extracellular signal-regulated kinase
Abstract: The occurrence of chemoresistance is a serious problem in the treatment of cancer, urging the need for secondand third-line treatment options that rely on different cell death pathways to overcome previously acquired resistance mechanisms. The inhibition of proteasomal activity by specific proteasome inhibitors or cross-reactivity of certain protease inhibitors with proteasomal enzymes recently became of interest because of the anti-tumoral properties of these agents. We tested the proteasome inhibitor bortezomib and the HIV protease inhibitor nelfinavir on human cervical cancer cells. Both drugs induced cell cycle arrest in cervical cancer cells, as reflected by marked changes in the expression of cell cycle-regulatory cyclins and ensuing mitochondrial-independent apoptosis. Upregulation of the molecular chaperone BiP and the cell stress marker ATF3 indicated induction of the unfolded protein response (UPR) as the main cause of apoptosis induced by these drugs in cervical cancer cells. Unlike in leukemia cells, bortezomib mainly inhibited the caspase-like activity of the proteasome in cervical cancer cells. Nelfinavir exhibited no effects on proteasomal activity in cervical cancer cells and leukemia cells. Although both bortezomib and nelfinavir acted on cisplatin-resistant cervical cancer cells (SiHa), neither of the drugs induced a sensitization to cisplatin treatment. Instead, both drugs could effectively be combined with each other, and enhanced the efficacy of an apoptosis-inducing TRAIL receptor antibody. These results suggest that both bortezomib and nelfinavir are effective agents against chemoresistant cervical cancer cells and might be of interest for clinical studies on cervical cancer patients with recurrent or metastatic cancer.
Export Options
About this article
Cite this article as:
Bruning A., Vogel M., Mylonas I., Friese K. and Burges A., Bortezomib Targets the Caspase-Like Proteasome Activity in Cervical Cancer Cells, Triggering Apoptosis That Can be Enhanced by Nelfinavir, Current Cancer Drug Targets 2011; 11 (7) . https://dx.doi.org/10.2174/156800911796798913
DOI https://dx.doi.org/10.2174/156800911796798913 |
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
-
Oral Inflammation and Bacteremia: Implications for Chronic and Acute Systemic Diseases Involving Major Organs
Cardiovascular & Hematological Disorders-Drug Targets Pathology of the HPV-associated Oropharyngeal Carcinoma
Current Cancer Therapy Reviews Venous Collateral Circulation of the Extracranial Cerebrospinal Outflow Routes
Current Neurovascular Research Meet Our Editorial Board Member:
Applied Clinical Research, Clinical Trials and Regulatory Affairs C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside
Current Neuropharmacology Polyphenols and Aging
Current Aging Science ING Proteins as Potential Anticancer Drug Targets
Current Drug Targets Cell Elimination as a Strategy for Repair in Acute Spinal Cord Injury
Current Pharmaceutical Design Pharmacological Potentials and Nutritional Values of Tropical and Subtropical Fruits of India: Emphasis on their Anticancer Bioactive Components
Recent Patents on Anti-Cancer Drug Discovery Viral Disorder or Disordered Viruses: Do Viral Proteins Possess Unique Features?
Protein & Peptide Letters Current Issues in the Utility of Blood Oxygen Level Dependent MRI for the Assessment of Modulations in Tumor Oxygenation
Current Medical Imaging Sequential Bilateral Internal Jugular Vein Thrombosis: A Case Report and Review of this Rare Medical Entity
Vascular Disease Prevention (Discontinued) Gene Expression Abnormalities in Thymoma
Current Pharmacogenomics Cervical Cancer Diagnosis: Insights into Biochemical Biomarkers and Imaging Techniques
Combinatorial Chemistry & High Throughput Screening Immune Modulation by Ionizing Radiation and its Implications for Cancer Immunotherapy
Current Pharmaceutical Design The Application of lncRNAs in Cancer Treatment and Diagnosis
Recent Patents on Anti-Cancer Drug Discovery Angiogenesis Markers in Gynecological Tumors and Patents for Anti- Angiogenic Approach: Review
Recent Patents on Anti-Cancer Drug Discovery Is There an Increased Risk of Lymphoma and Malignancies Under Anti- TNF Therapy in IBD?
Current Drug Targets Potential Non-coding RNAs from Microorganisms and their Therapeutic Use in the Treatment of Different Human Cancers
Current Gene Therapy Immunogenic Issues Concerning Recombinant Adeno-Associated Virus Vectors for Gene Therapy
Current Gene Therapy