Abstract
Recently we have reported potent anti-cancer actions of various steroidal Na+/K+ ATPase inhibitors in multiple cell lines. Furthermore, the most powerful compound identified in this study, the 3-[(R)-3-pyrrolidinyl]oxime derivative (3-R-POD), was highly effective in various tumor cell lines in vitro, and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. In the present study we have addressed the molecular mechanisms implicated in the anti-cancer actions of 3-R-POD. We report here that 3-R-POD induces strong apoptotic responses in A549 lung- and in DU145 prostate- cancer cells. These effects are accompanied by significant upregulation of caspase-3 activity. Focussing on A549 cells, we further demonstrate late downregulation of BCL-2- and upregulation of c-Fos- gene transcription. In addition, the steroidal Na+/K+ ATPase inhibitor induced late de-phosphorylation of Focal Adhesion Kinase (FAK) and activation of p38 MAPK. Our findings suggest that the steroidal Na+/K+ ATPase inhibitor 3-R-POD induces apoptosis, paralleled by altered BCL-2 and c-Fos gene transcription, inhibition of the pro-survival FAK signalling, up-regulation of the pro-apoptotic p38 MAPK pathway and stimulation of caspase-3 activity.
Keywords: Apoptosis, lung cancer, prostate cancer, signaling, steroidal Na+/K+ ATPase inhibitor.
Anti-Cancer Agents in Medicinal Chemistry
Title:A Steroidal Na+/K+ ATPase Inhibitor Triggers Pro-apoptotic Signaling and Induces Apoptosis in Prostate and Lung Tumor Cells
Volume: 14 Issue: 8
Author(s): Sabina Honisch, Saad Alkahtani, Michalis Kounenidakis, Guilai Liu, Saud Alarifi, Hamad Al-Yahya, Konstantinos Dimas, Abdullah A. AlKahtane, Kyriakos C. Prousis, Bader Al-Dahmash, Theodora Calogeropoulou, Konstantinos Alevizopoulos, Florian Lang and Christos Stournaras
Affiliation:
Keywords: Apoptosis, lung cancer, prostate cancer, signaling, steroidal Na+/K+ ATPase inhibitor.
Abstract: Recently we have reported potent anti-cancer actions of various steroidal Na+/K+ ATPase inhibitors in multiple cell lines. Furthermore, the most powerful compound identified in this study, the 3-[(R)-3-pyrrolidinyl]oxime derivative (3-R-POD), was highly effective in various tumor cell lines in vitro, and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. In the present study we have addressed the molecular mechanisms implicated in the anti-cancer actions of 3-R-POD. We report here that 3-R-POD induces strong apoptotic responses in A549 lung- and in DU145 prostate- cancer cells. These effects are accompanied by significant upregulation of caspase-3 activity. Focussing on A549 cells, we further demonstrate late downregulation of BCL-2- and upregulation of c-Fos- gene transcription. In addition, the steroidal Na+/K+ ATPase inhibitor induced late de-phosphorylation of Focal Adhesion Kinase (FAK) and activation of p38 MAPK. Our findings suggest that the steroidal Na+/K+ ATPase inhibitor 3-R-POD induces apoptosis, paralleled by altered BCL-2 and c-Fos gene transcription, inhibition of the pro-survival FAK signalling, up-regulation of the pro-apoptotic p38 MAPK pathway and stimulation of caspase-3 activity.
Export Options
About this article
Cite this article as:
Honisch Sabina, Alkahtani Saad, Kounenidakis Michalis, Liu Guilai, Alarifi Saud, Al-Yahya Hamad, Dimas Konstantinos, AlKahtane A. Abdullah, Prousis C. Kyriakos, Al-Dahmash Bader, Calogeropoulou Theodora, Alevizopoulos Konstantinos, Lang Florian and Stournaras Christos, A Steroidal Na+/K+ ATPase Inhibitor Triggers Pro-apoptotic Signaling and Induces Apoptosis in Prostate and Lung Tumor Cells, Anti-Cancer Agents in Medicinal Chemistry 2014; 14 (8) . https://dx.doi.org/10.2174/1871520614666140618114418
DOI https://dx.doi.org/10.2174/1871520614666140618114418 |
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
-
Neuroprotective Effects of Quercetin: From Chemistry to Medicine
CNS & Neurological Disorders - Drug Targets Highly Disordered Proteins in Prostate Cancer
Current Protein & Peptide Science Biomarker Assessment in Nutritional Modulation of Oxidative Stress-Induced Cancer Development by Lipid-Related Bioactive Molecules
Recent Patents on Anti-Cancer Drug Discovery Prioritizing Disease Genes by Using Search Engine Algorithm
Current Bioinformatics Impact of Epigenetic Dietary Components on Cancer through Histone Modifications
Current Medicinal Chemistry Intramolecular Cyclisation of β-Aryl-β-Amino Acids in the Design of Novel Heterocyclic Systems with Therapeutic Interest: An Unfailing Source of Diversity
Current Medicinal Chemistry Cognition and Emotions in Recurrent Depressive Disorders - The Role of Inflammation and the Kynurenine Pathway
Current Pharmaceutical Design Low Testosterone and Diabetes
Current Diabetes Reviews Algal Biorefinery for the Extraction of Bioactive Compounds
Current Bioactive Compounds Multiple Means by Which Nitric Oxide can Antagonize Photodynamic Therapy
Current Medicinal Chemistry Studies on Structures and Functions of Kinases leading to Prostate Cancer and Their Inhibitors
Current Enzyme Inhibition Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?
Anti-Cancer Agents in Medicinal Chemistry Tumor Angiogenesis and VEGFR-2: Mechanism, Pathways and Current Biological Therapeutic Interventions
Current Drug Metabolism Circulating Tumor Cells (CTCs) as a Liquid Biopsy Material and Drug Target
Current Drug Targets Prostate Cancer: Biology, Incidence, Detection Methods, Treatment Methods, and Vaccines
Current Topics in Medicinal Chemistry Development of a Web-Enabled SVR-Based Machine Learning Platform and its Application on Modeling Transgene Expression Activity of Aminoglycoside-Derived Polycations
Combinatorial Chemistry & High Throughput Screening Role of NF-κB in the Regulation of Cytochrome P450 Enzymes
Current Drug Metabolism Editorial [Hot Topic: Transription Factors and their Modulated Genes as Targets for Chemoprevention (Guest Editor: Chuanshu Huang)]
Current Cancer Drug Targets Obesity Modulation - The Role in Carcinogenesis
Anti-Cancer Agents in Medicinal Chemistry Endocrine Therapy for Advanced Breast Cancer: Beyond Tamoxifen and Aromatase Inhibitors
Current Cancer Therapy Reviews