Abstract
Background: One of the main reasons for the poor survival rates of pancreatic cancer patients is the development of gemcitabine resistance, indicating that novel treatment strategies that have the ability to improve gemcitabine sensitivity are in need to combat this devastating disease.
Methods: TCGA PAAD data was used to determine the clinicopathological significance of high RRM2 (Ribonucleotide reductase subunit M2) expression for Pancreatic Ductal Adenocarcinoma (PDAC). The effects of GW8510 and gemcitabine on PANC-1 cell viability were determined using WST-8 assay. The potential synergistic interaction between GW8510 and gemcitabine was evaluated by the Combination Index (CI) analysis. The effects of GW8510 treatment on apoptosis, cell cycle, and cell migration, either in combination with gemcitabine or alone, were investigated. The effect of GW8510 on RRM2 protein levels was evaluated using ELISA assay.
Results: RRM2 is significantly over-expressed in PDAC compared to healthy pancreatic tissues (p <0.0001). RRM2 mRNA expression was found to be significantly correlated with the overall survival rate of patients (HR=2.17 [1.44-3.27], p=0.00016) and the pathological stages of the disease (p=0.0054). GW8510 significantly decreased the RRM2 protein levels compared to the control. Cell viability analysis showed that GW8510 has a similar effect to gemcitabine in inhibiting PANC-1 cell viability. GW8510 was found to synergize with gemcitabine to inhibit PANC-1 cell viability and migration. However, the effects of GW8510 on PANC-1 cells could not be explained by induction of apoptosis or cell cycle arrest.
Conclusion: Targeting RRM2 using GW8510 may have the potential to increase gemcitabine sensitivity in pancreatic cancer.
Keywords: GW8510, RRM2, PANC-1, gemcitabine, survival, mRNA expression.
Anti-Cancer Agents in Medicinal Chemistry
Title:Synergistic Interactions between GW8510 and Gemcitabine in an In Vitro Model of Pancreatic Cancer
Volume: 21 Issue: 16
Author(s): Duygu Gençalp Rüstem, Sevcan Atay, Hikmet Hakan Aydin and Handan Ak*
Affiliation:
- Department of Medical Biochemistry, Ege University Faculty of Medicine, Bornova, Izmir,Turkey
Keywords: GW8510, RRM2, PANC-1, gemcitabine, survival, mRNA expression.
Abstract:
Background: One of the main reasons for the poor survival rates of pancreatic cancer patients is the development of gemcitabine resistance, indicating that novel treatment strategies that have the ability to improve gemcitabine sensitivity are in need to combat this devastating disease.
Methods: TCGA PAAD data was used to determine the clinicopathological significance of high RRM2 (Ribonucleotide reductase subunit M2) expression for Pancreatic Ductal Adenocarcinoma (PDAC). The effects of GW8510 and gemcitabine on PANC-1 cell viability were determined using WST-8 assay. The potential synergistic interaction between GW8510 and gemcitabine was evaluated by the Combination Index (CI) analysis. The effects of GW8510 treatment on apoptosis, cell cycle, and cell migration, either in combination with gemcitabine or alone, were investigated. The effect of GW8510 on RRM2 protein levels was evaluated using ELISA assay.
Results: RRM2 is significantly over-expressed in PDAC compared to healthy pancreatic tissues (p <0.0001). RRM2 mRNA expression was found to be significantly correlated with the overall survival rate of patients (HR=2.17 [1.44-3.27], p=0.00016) and the pathological stages of the disease (p=0.0054). GW8510 significantly decreased the RRM2 protein levels compared to the control. Cell viability analysis showed that GW8510 has a similar effect to gemcitabine in inhibiting PANC-1 cell viability. GW8510 was found to synergize with gemcitabine to inhibit PANC-1 cell viability and migration. However, the effects of GW8510 on PANC-1 cells could not be explained by induction of apoptosis or cell cycle arrest.
Conclusion: Targeting RRM2 using GW8510 may have the potential to increase gemcitabine sensitivity in pancreatic cancer.
Export Options
About this article
Cite this article as:
Rüstem Gençalp Duygu , Atay Sevcan , Aydin Hakan Hikmet and Ak Handan *, Synergistic Interactions between GW8510 and Gemcitabine in an In Vitro Model of Pancreatic Cancer, Anti-Cancer Agents in Medicinal Chemistry 2021; 21 (16) . https://dx.doi.org/10.2174/1871520621999210104201553
DOI https://dx.doi.org/10.2174/1871520621999210104201553 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Discovery of Lead compounds targeting transcriptional regulation
Transcriptional regulation plays key physiological functions in body growth and development. Transcriptional dysregulation is one of the important biomarkers of tumor genesis and progression, which is involved in regulating tumor cell processes such as cell proliferation, differentiation, and apoptosis. Additionally, it plays a pivotal role in angiogenesis and promotes tumor ...read more
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 that aid in stabilizing chromosomal makeup. The resynthesis of telomeres is supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no telomerase activity in human somatic cells, but the stem cells and germ cells undergo ...read more
Innovative targets in medicinal chemistry
Medicinal chemistry continuously evolves in response to emerging healthcare needs and advancements in scientific understanding. This special issue explores the current landscape of innovative targets in medicinal chemistry, highlighting the quest for novel therapeutic avenues. From traditional drug targets such as enzymes and receptors to emerging targets like protein-protein interactions ...read more
Metalloenzymes and Cancer: Μetalloenzyme Ιnhibitors and Artificial Metalloenzymes as anti-cancer agents
Metalloenzymes are enzymes containing metal ions, which are directly bound to the enzyme and play a role in promoting catalysis. About one-third of all enzymes known so far are metalloenzymes [1]. Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many ...read more
![Wayfinder Image](/images/wayfinder.jpg)
- 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
-
Update on the Rheumatologic Manifestations of Malignancy
Current Cancer Therapy Reviews Free Radicals and Antioxidants: How to Reestablish Redox Homeostasis in Chronic Diseases?
Current Medicinal Chemistry An Overview of Targeting Legumain for Inhibiting Cancers
Current Pharmaceutical Design Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?
Current Medicinal Chemistry Antifolate Inhibitors of Thymidylate Synthase as Anticancer Drugs
Mini-Reviews in Medicinal Chemistry 3-Carboranyl Thymidine Analogues (3CTAs) and Other Boronated Nucleosides for Boron Neutron Capture Therapy
Anti-Cancer Agents in Medicinal Chemistry Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins
Recent Patents on Anti-Cancer Drug Discovery EMT Blockage Strategies: Targeting Akt Dependent Mechanisms for Breast Cancer Metastatic Behaviour Modulation
Current Gene Therapy Natural Cyclic Peptides as Clinical and Future Therapeutics
Current Organic Chemistry Scaffold Vascularization: A Challenge for Three-Dimensional Tissue Engineering
Current Medicinal Chemistry Programming Apoptosis and Autophagy with Novel Approaches for Diabetes Mellitus
Current Neurovascular Research An Overview on Pyranocoumarins: Synthesis and Biological Activities
Current Organic Chemistry Pancreatic β-Cells and Type 2 Diabetes Development
Current Diabetes Reviews Pulmonary Neuroendocrine Cell System in Health and Disease
Current Respiratory Medicine Reviews The Importance of Growth Hormone (GH) and GH Secretagogues for Bone Mass and Density
Current Pharmaceutical Design Sirtuin-1 and HIV-1: An Overview
Current Drug Targets Intracellular Bioinorganic Chemistry and Cross Talk Among Different -Omics
Current Topics in Medicinal Chemistry TRIM45 Suppresses the Development of Non-small Cell Lung Cancer
Current Molecular Medicine Role of NADPH Quinone Reductase 1 (NQO1) Polymorphism in Prevention, Diagnosis, and Treatment of Gastrointestinal Cancers
Current Cancer Drug Targets Potential Role of TRAIL in the Management of Autoimmune Diabetes Mellitus
Current Pharmaceutical Design