Abstract
Available chemotherapeutics take advantage of the fast proliferation of cancer cells. Consequently slow growth makes androgen refractory prostate cancer resistant towards available drugs. No treatment is available at the present, when the cancer has developed metastases outside the prostate (T4 stage). Cytotoxins killing cells irrespective of the phase of the cell cycle will be able to kill slowly proliferating prostate cancer cells. Lack of selectivity, however, prevents their use as systemic drugs. Prostate cancer cells secrete characteristic proteolytic enzymes, e.g. PSA and hK2, with unusual substrate specificity. Conjugation of cytotoxins with peptides, which are selective substrates for PSA or hK2, will afford prodrugs, from which the active drug only will be released in close vicinity of the cancer cells. Based on this strategy prodrugs targeted at prostate cancer cells have been constructed and evaluated as potential drugs for prostate cancer. The potency of the thapsigargins as apoptotic agents make these naturally occurring sesquiterpene lactones attractive lead compounds. Intensive studies on structure-activity relationships and chemistry of the thapsigargins have enabled construction of potent derivatives enabling conjugation with peptides. Studies on the mechanism of action of the thapsigargins have revealed that the cytoxicity is based on their ability to inhibit the intracellular sarco-/endoplasmtic calcium pump.
Keywords: Prostate cancer, targeted drugs, thapsigargin, PSA, hK2, Prodrug, SERCA
Anti-Cancer Agents in Medicinal Chemistry
Title: A Trojan Horse in Drug Development: Targeting of Thapsigargins Towards Prostate Cancer Cells
Volume: 9 Issue: 3
Author(s): S. Brogger Christensen, Dorthe Mondrup Skytte, Samuel R. Denmeade, Craig Dionne, Jesper Vuust Moller, Poul Nissen and John T. Isaacs
Affiliation:
Keywords: Prostate cancer, targeted drugs, thapsigargin, PSA, hK2, Prodrug, SERCA
Abstract: Available chemotherapeutics take advantage of the fast proliferation of cancer cells. Consequently slow growth makes androgen refractory prostate cancer resistant towards available drugs. No treatment is available at the present, when the cancer has developed metastases outside the prostate (T4 stage). Cytotoxins killing cells irrespective of the phase of the cell cycle will be able to kill slowly proliferating prostate cancer cells. Lack of selectivity, however, prevents their use as systemic drugs. Prostate cancer cells secrete characteristic proteolytic enzymes, e.g. PSA and hK2, with unusual substrate specificity. Conjugation of cytotoxins with peptides, which are selective substrates for PSA or hK2, will afford prodrugs, from which the active drug only will be released in close vicinity of the cancer cells. Based on this strategy prodrugs targeted at prostate cancer cells have been constructed and evaluated as potential drugs for prostate cancer. The potency of the thapsigargins as apoptotic agents make these naturally occurring sesquiterpene lactones attractive lead compounds. Intensive studies on structure-activity relationships and chemistry of the thapsigargins have enabled construction of potent derivatives enabling conjugation with peptides. Studies on the mechanism of action of the thapsigargins have revealed that the cytoxicity is based on their ability to inhibit the intracellular sarco-/endoplasmtic calcium pump.
Export Options
About this article
Cite this article as:
Christensen Brogger S., Skytte Mondrup Dorthe, Denmeade R. Samuel, Dionne Craig, Moller Vuust Jesper, Nissen Poul and Isaacs T. John, A Trojan Horse in Drug Development: Targeting of Thapsigargins Towards Prostate Cancer Cells, Anti-Cancer Agents in Medicinal Chemistry 2009; 9 (3) . https://dx.doi.org/10.2174/1871520610909030276
DOI https://dx.doi.org/10.2174/1871520610909030276 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...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
-
Targeting JAK/STAT Signaling Pathway in Inflammatory Diseases
Current Signal Transduction Therapy The Immune System of Cancer Patients
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Apoptosis Imaging to Monitor Cancer Therapy: The Road to Fast Treatment Evaluation?
Current Pharmaceutical Biotechnology Associations of Body Mass Index and Obesity-Related Genetic Variants with Serum Metabolites
Current Metabolomics Protein Kinase C Isoforms - Implications to Thrombosis
Current Signal Transduction Therapy Click Chemistry, A Potent Tool in Medicinal Sciences
Current Medicinal Chemistry 86Y Based PET Radiopharmaceuticals: Radiochemistry and Biological Applications
Medicinal Chemistry Structure-based Design on Anticancer Drug Discovery
Current Topics in Medicinal Chemistry Quality of Education and Memory Test Performance in Older Men: The New York University Paragraph Recall Test Normative Data
Current Alzheimer Research Recent Evidence on the Role of Dietary PUFAs in Cancer Development and Prevention
Current Medicinal Chemistry Recent Clinical Evidence in Bisphosphonate-related Osteomyelitis of the Jaw: Focus on Risk, Prevention and Treatment
Reviews on Recent Clinical Trials Adrenomedullin: A Tumor Progression Factor via Angiogenic Control
Current Cancer Drug Targets Disease-Related Changes in TRPV1 Expression and Its Implications for Drug Development
Current Topics in Medicinal Chemistry Combating P-glycoprotein-Mediated Multidrug Resistance Using Therapeutic Nanoparticles
Current Pharmaceutical Design The Insulin-Like Growth Factor (IGF) Signaling Pathway: Strategies for Successful Therapeutic Tasks in Cancer Treatment
Current Cancer Therapy Reviews In Situ Gene Therapy for Prostate Cancer
Current Gene Therapy Recent Advances of Natural and Synthetic β-Carbolines as Anticancer Agents
Anti-Cancer Agents in Medicinal Chemistry Journey of 2′-deoxy-2′-fluoro-5-methyl-1-β-D-arabinofuranosyluracil (FMAU): from Antiviral Drug to PET Imaging Agent
Current Medicinal Chemistry Fibroblast Growth Factor-2 Antagonist and Antiangiogenic Activity of Long-Pentraxin 3-Derived Synthetic Peptides
Current Pharmaceutical Design Targeting DNA Minor Groove by Hybrid Molecules as Anticancer Agents
Current Medicinal Chemistry