Abstract
Aurora Kinase (AK) based therapy targeting AK-A & B is effective against some cancers. We have explored its potential against previously unreported incurable, metastatic androgen depletion independent Prostate Cancer (ADIPC). We used androgen sensitive (AS) and ADI lines derived from Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. The relevance of this model was unequivocally established through focussed array, quantitative PCR and western blotting studies; significantly greater alteration of genes (fold change and number) representing major cancer pathways was shown in ADI cells compared to AS lines. A marked enhancement of in vivo growth of the ADI subline showing the greatest degree of gene modulations [TRAMP C1 (TC1)-T5: TC1-T5] reflected this. In contrast to the parental AS TC1 line, TC1-T5 cells grew with 100% incidence in the prostate, as lung pseudometastases and migrated to the bone and other soft tissues. The potential involvement of AKs in this transition was indicated by the significant upregulation of AK-A/B and their downstream regulators, survivin and phosphorylated-histone H3 in TC1-T5 cells compared to TC1 cells. This led to enhanced sensitivity of TC1-T5 cells to the pan-AK inhibitor, VX680 and to significant reduction in in vivo tumour growth rates when AK-A and/or B were downregulated in TC1-T5 cells. This cell growth inhibition was markedly enhanced when both AKs were downregulated and also led to substantially greater sensitivity of these cells to docetaxel, the only chemotherapeutic with activity against ADI PC. Finally, use of VX680 with docetaxel led to impressive synergies suggesting promise for treating clinical ADI metastatic PC.
Keywords: Aurora kinases, Cancer, chemotherapy, combination therapy, docetaxel, prostate cancer, targeted molecular therapy, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP), Androgen Sensitive, Androgen Depletion Independent, Combination Index, Dose Reduction Index, Horse Radish Peroxidase, Harris' Hematoxylin and Eosin, Inner Centromere Protein
Current Cancer Drug Targets
Title: Targeting Aurora Kinases: A Novel Approach to Curb the Growth & Chemoresistance of Androgen Refractory Prostate Cancer
Volume: 12 Issue: 2
Author(s): V. Jeet, P. J. Russell, N. D. Verma and A. Khatri
Affiliation:
Keywords: Aurora kinases, Cancer, chemotherapy, combination therapy, docetaxel, prostate cancer, targeted molecular therapy, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP), Androgen Sensitive, Androgen Depletion Independent, Combination Index, Dose Reduction Index, Horse Radish Peroxidase, Harris' Hematoxylin and Eosin, Inner Centromere Protein
Abstract: Aurora Kinase (AK) based therapy targeting AK-A & B is effective against some cancers. We have explored its potential against previously unreported incurable, metastatic androgen depletion independent Prostate Cancer (ADIPC). We used androgen sensitive (AS) and ADI lines derived from Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. The relevance of this model was unequivocally established through focussed array, quantitative PCR and western blotting studies; significantly greater alteration of genes (fold change and number) representing major cancer pathways was shown in ADI cells compared to AS lines. A marked enhancement of in vivo growth of the ADI subline showing the greatest degree of gene modulations [TRAMP C1 (TC1)-T5: TC1-T5] reflected this. In contrast to the parental AS TC1 line, TC1-T5 cells grew with 100% incidence in the prostate, as lung pseudometastases and migrated to the bone and other soft tissues. The potential involvement of AKs in this transition was indicated by the significant upregulation of AK-A/B and their downstream regulators, survivin and phosphorylated-histone H3 in TC1-T5 cells compared to TC1 cells. This led to enhanced sensitivity of TC1-T5 cells to the pan-AK inhibitor, VX680 and to significant reduction in in vivo tumour growth rates when AK-A and/or B were downregulated in TC1-T5 cells. This cell growth inhibition was markedly enhanced when both AKs were downregulated and also led to substantially greater sensitivity of these cells to docetaxel, the only chemotherapeutic with activity against ADI PC. Finally, use of VX680 with docetaxel led to impressive synergies suggesting promise for treating clinical ADI metastatic PC.
Export Options
About this article
Cite this article as:
Jeet V., J. Russell P., D. Verma N. and Khatri A., Targeting Aurora Kinases: A Novel Approach to Curb the Growth & Chemoresistance of Androgen Refractory Prostate Cancer, Current Cancer Drug Targets 2012; 12 (2) . https://dx.doi.org/10.2174/156800912799095180
DOI https://dx.doi.org/10.2174/156800912799095180 |
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
-
The Synergistic Effects of DNA-Targeted Chemotherapeutics and Histone Deacetylase Inhibitors As Therapeutic Strategies for Cancer Treatment
Current Medicinal Chemistry Targeting Heme for the Identification of Cytotoxic Agents
Anti-Cancer Agents in Medicinal Chemistry The Prevention and Treatment of Delirium in Elderly Patients Following Hip Fracture Surgery
Recent Patents on CNS Drug Discovery (Discontinued) Nanoparticles, Neurotoxicity and Neurodegenerative Diseases
Current Drug Metabolism Post-Wortmannin Era: Novel Phosphoinositide 3-Kinase Inhibitors with Potential Therapeutic Applications
Current Enzyme Inhibition Beta-Emitting Radionuclides for Peptide Receptor Radionuclide Therapy
Current Topics in Medicinal Chemistry CD26/Dipeptidyl Peptidase IV as a Novel Therapeutic Target for Cancer and Immune Disorders
Mini-Reviews in Medicinal Chemistry Angiogenesis Inhibition: State of the Art, Forgotten Strategies and New Perspectives in Cancer Therapy
Current Cancer Therapy Reviews Glucocorticoids Pharmacology: Past, Present and Future
Current Pharmaceutical Design Regulation of Glycolytic and Mitochondrial Metabolism by Ras
Current Pharmaceutical Biotechnology Oncologic Imaging End-Points for the Assessment of Therapy Response
Recent Patents on Anti-Cancer Drug Discovery PET Tracers for Serotonin Receptors and Their Applications
Central Nervous System Agents in Medicinal Chemistry Editorial [Hot Topic: Transription Factors and their Modulated Genes as Targets for Chemoprevention (Guest Editor: Chuanshu Huang)]
Current Cancer Drug Targets Editorial (Hot Topic Potential Value and Limitation of Dual Inhibitors of PI3K and mTOR in the Treatment of Cancer)
Current Cancer Drug Targets Next-Generation Anticancer Metallodrugs
Current Topics in Medicinal Chemistry An Overview on Different Classes of Viral Entry and Respiratory Syncitial Virus (RSV) Fusion Inhibitors
Current Medicinal Chemistry Permanent Implantation as Brachytherapy Technique for Prostate Carcinoma-Review of Clinical Trials and Guidelines
Reviews on Recent Clinical Trials Towards Understanding the Role of Cancer-Associated Inflammation in Chemoresistance
Current Pharmaceutical Design Regulation of Bcl-2 Family Proteins by Posttranslational Modifications
Current Molecular Medicine Molecular Pathways in the Progression of Hormone-Independent and Metastatic Prostate Cancer
Current Cancer Drug Targets