Abstract
Background: EGFR tyrosine kinase inhibitors (TKIs) are widely used for advanced nonsmall cell lung cancer (NSCLC) patients with a sensitizing EGFR mutation and provide a promising treatment strategy. However, acquired resistance to EGFR-TKIs restricts their application. The mechanisms underlying acquired resistance to TKIs have been explored and Phosphoinositide 3- kinase (PI3K)/Akt/mTOR pathway plays a very important role in NSCLC development as well as EGFR-TKI resistance. Polyphyllin II(PP II) is the main steroidal saponin constituent which derives from the root of Paris polychylia.
Objective: We examined the sensitizing effect of PP II to gefitinib on proliferation, apoptosis, PI3K/Akt/mTOR signaling pathway and tumor growth on gefitinib-resistant NSCLC in vitro and in vivo. Methods: Gefitinib-resistant PC-9/ZD cells and gefitinib-sensitive PC-9 cells were used. In the absence of PI3K siRNA, MTT assay, Annexin V/PI analyses, Western blot, and Immunohistochemistry analysis by TUNEL assays for xenograft model were carried out. Results: PP II promoted the anti-proliferative effects of gefitinib and gefitinib-induced apoptosis via activation of caspases and cleavage of PARP. PP II elevated sensitization of gefitinib through targeting the PI3K/Akt/mTOR. PP II with gefitinib treatment was more effective in inhibiting tumor growth and PI3K inactivation on gefitinib-resistant xenograft. Conclusion: The results indicated that PP II elevated sensitization of drug-resistant PC-9/ZD cells to gefitinib through the inhibition of PI3K/Akt/mTOR signaling pathway. It provides a potential new strategy to overcome gefitinib resistance for EGFR-TKI resistant NSCLC.Keywords: PI3K, drug-resistance, gefitinib, NSCLC, polyphyllin, apoptosis.
Current Cancer Drug Targets
Title:Polyphyllin II Restores Sensitization of the Resistance of PC-9/ZD Cells to Gefitinib by a Negative Regulation of the PI3K/Akt/mTOR Signaling Pathway
Volume: 17 Issue: 4
Author(s): Ruzhen Zheng, Hao Jiang*, Jinhui Li, Xinge Liu and Hongwei Xu
Affiliation:
- Department of Oncology, Zhejiang Hospital, No.12 Lingyin Road, Hangzhou, Zhejiang 310013,China
Keywords: PI3K, drug-resistance, gefitinib, NSCLC, polyphyllin, apoptosis.
Abstract: Background: EGFR tyrosine kinase inhibitors (TKIs) are widely used for advanced nonsmall cell lung cancer (NSCLC) patients with a sensitizing EGFR mutation and provide a promising treatment strategy. However, acquired resistance to EGFR-TKIs restricts their application. The mechanisms underlying acquired resistance to TKIs have been explored and Phosphoinositide 3- kinase (PI3K)/Akt/mTOR pathway plays a very important role in NSCLC development as well as EGFR-TKI resistance. Polyphyllin II(PP II) is the main steroidal saponin constituent which derives from the root of Paris polychylia.
Objective: We examined the sensitizing effect of PP II to gefitinib on proliferation, apoptosis, PI3K/Akt/mTOR signaling pathway and tumor growth on gefitinib-resistant NSCLC in vitro and in vivo. Methods: Gefitinib-resistant PC-9/ZD cells and gefitinib-sensitive PC-9 cells were used. In the absence of PI3K siRNA, MTT assay, Annexin V/PI analyses, Western blot, and Immunohistochemistry analysis by TUNEL assays for xenograft model were carried out. Results: PP II promoted the anti-proliferative effects of gefitinib and gefitinib-induced apoptosis via activation of caspases and cleavage of PARP. PP II elevated sensitization of gefitinib through targeting the PI3K/Akt/mTOR. PP II with gefitinib treatment was more effective in inhibiting tumor growth and PI3K inactivation on gefitinib-resistant xenograft. Conclusion: The results indicated that PP II elevated sensitization of drug-resistant PC-9/ZD cells to gefitinib through the inhibition of PI3K/Akt/mTOR signaling pathway. It provides a potential new strategy to overcome gefitinib resistance for EGFR-TKI resistant NSCLC.Export Options
About this article
Cite this article as:
Zheng Ruzhen, Jiang Hao*, Li Jinhui, Liu Xinge and Xu Hongwei, Polyphyllin II Restores Sensitization of the Resistance of PC-9/ZD Cells to Gefitinib by a Negative Regulation of the PI3K/Akt/mTOR Signaling Pathway, Current Cancer Drug Targets 2017; 17 (4) . https://dx.doi.org/10.2174/1568009616666161213141608
DOI https://dx.doi.org/10.2174/1568009616666161213141608 |
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
-
Younger for Longer: Insulin Signalling, Immunity and Ageing
Current Aging Science Magnetic Nanoparticles: A Review on Stratagems of Fabrication an d its Biomedical Applications
Recent Patents on Drug Delivery & Formulation Raman Molecular Imaging of Cells and Tissues: Towards Functional Diagnostic Imaging Without Labeling
Current Pharmaceutical Biotechnology Immunotherapy of Human Cancers Using Gene Modified T Lymphocytes
Current Gene Therapy Use of Complementary Medicine Amongst Patients on Antiretroviral Drugs in an HIV Treatment Centre in Lagos, Nigeria
Current Drug Safety Recent Advance in Drug Development of Squamous Cell Carcinoma
Anti-Cancer Agents in Medicinal Chemistry MicroRNAs in Esophageal Adenocarcinoma: Functional Significance and Potential for the Development of New Molecular Disease Markers
Current Pharmaceutical Design In vitro activity and Cytotoxicity of Crocus sativus Extract against Leihmania Major (MRHO/IR/75/ER)
Infectious Disorders - Drug Targets Targeting Tumor-Related Immunosuppression for Cancer Immunotherapy
Endocrine, Metabolic & Immune Disorders - Drug Targets Cholinergic Receptors as Target for Cancer Therapy in a Systems Medicine Perspective
Current Molecular Medicine Meet Our Editorial Board Member
MicroRNA Targeting Tumor Proteasome with Traditional Chinese Medicine
Current Drug Discovery Technologies Exosomal MicroRNAs in Tumoral U87 MG Versus Normal Astrocyte Cells
MicroRNA Redox Regulation in the Base Excision Repair Pathway: Old and New Players as Cancer Therapeutic Targets
Current Medicinal Chemistry Novel Immunotherapeutic Strategies for Invasive Fungal Disease
Current Drug Targets - Cardiovascular & Hematological Disorders Polysaccharide Colloids as Smart Vehicles in Cancer Therapy
Current Pharmaceutical Design Pharmacogenetics of Phase I and Phase II Drug Metabolism
Current Pharmaceutical Design Cannabis-Derived Substances in Cancer Therapy – An Emerging Anti- Inflammatory Role for the Cannabinoids
Current Clinical Pharmacology Ciprofloxacin Stress Proteome of the Extended-Spectrum β-lactamase Producing Escherichia coli from Slaughtered Pigs
Current Proteomics A Viewpoint on Potential Biomarkers for Infectious COVID-19 Severity: An Updated Literature Survey
Infectious Disorders - Drug Targets