Abstract
Background: Multi-drug resistance (MDR) remains a major impediment in cancer therapy. A major goal for scientists is to discover more effective compounds that are able to circumvent MDR and simultaneously have minimal adverse side effects.
Objective: In the present study, we aim to determine the anti-MDR effects of pyramidatine (Z88), a cinnamic acid-derived bisamide compound isolated from the leaves of Aglaia perviridis, on KB/VCR (vincristineresistant human oral cancer cells) and MCF-7/ADR (adriamycin-resistant human breast adenocarcinoma) cells.
Methods: Cell viability and average resistant fold (RF) of Z88 were examined by Cell Counting Kit-8 (CCK-8) assay. Flow cytometry, western blot, RT-PCR, Rhodamine 123 accumulation assay and P-glycoprotein (P-gp) ATPase assay were used to demonstrate the anti-MDR activity and mechanism of Z88.
Results: The average RF of Z88 is 0.09 and 0.51 in KB/VCR and MCF-7/ADR cells. A CCK-8 assay showed that Z88 could enhance the cytotoxicity of VCR toward KB/VCR cells. A FACS analysis revealed that Z88 could enhance the VCR-induced apoptosis as well as G2/M arrest in a dose-dependent manner in KB/VCR cells. Western blot results showed that the expression levels of PARP, Bax, and cyclin B1 all increased after treatment with 0.2 µmol/L (µM) of VCR combined with 10 µM of Z88 for 24 h in KB/VCR cells. Z88 also could enhance the accumulation of rhodamine 123. Further studies showed that Z88 could inhibit the verapamil stimulated Pgp ATPase activity. Additionally, qPCR detection and western blot assays revealed that Z88 could decrease the expression of P-gp at both RNA and protein level.
Conclusion: Z88 exerted potent anti-MDR activity in vitro and its mechanisms are associated with dualinhibition of the function and expression of P-gp. These findings encourage efforts to develop more effective reversal agents to circumvent MDR based on Z88.
Keywords: Aglaia perviridis, multi-drug resistance, KB/VCR cells, P-gp, reversal agent, pyramidatine.
Anti-Cancer Agents in Medicinal Chemistry
Title:Pyramidatine (Z88) Sensitizes Vincristine-Resistant Human Oral Cancer (KB/VCR) Cells to Chemotherapeutic Agents by Inhibition of P-glycoprotein
Volume: 18 Issue: 2
Author(s): Zulong Liu, Hengrui Zhu, Shijin Qu, Lisha Tang, Lihuan Cao, Wenbo Yu, Xianmei Yang, Songmin Jiang, Dayuan Zhu, Changheng Tan*Long Yu*
Affiliation:
- Department of Natural Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203,China
- State Key Laboratory of Genetic Engineering Institute of Genetics, School of Life Sciences Fudan University, Shanghai 200433,China
Keywords: Aglaia perviridis, multi-drug resistance, KB/VCR cells, P-gp, reversal agent, pyramidatine.
Abstract: Background: Multi-drug resistance (MDR) remains a major impediment in cancer therapy. A major goal for scientists is to discover more effective compounds that are able to circumvent MDR and simultaneously have minimal adverse side effects.
Objective: In the present study, we aim to determine the anti-MDR effects of pyramidatine (Z88), a cinnamic acid-derived bisamide compound isolated from the leaves of Aglaia perviridis, on KB/VCR (vincristineresistant human oral cancer cells) and MCF-7/ADR (adriamycin-resistant human breast adenocarcinoma) cells.
Methods: Cell viability and average resistant fold (RF) of Z88 were examined by Cell Counting Kit-8 (CCK-8) assay. Flow cytometry, western blot, RT-PCR, Rhodamine 123 accumulation assay and P-glycoprotein (P-gp) ATPase assay were used to demonstrate the anti-MDR activity and mechanism of Z88.
Results: The average RF of Z88 is 0.09 and 0.51 in KB/VCR and MCF-7/ADR cells. A CCK-8 assay showed that Z88 could enhance the cytotoxicity of VCR toward KB/VCR cells. A FACS analysis revealed that Z88 could enhance the VCR-induced apoptosis as well as G2/M arrest in a dose-dependent manner in KB/VCR cells. Western blot results showed that the expression levels of PARP, Bax, and cyclin B1 all increased after treatment with 0.2 µmol/L (µM) of VCR combined with 10 µM of Z88 for 24 h in KB/VCR cells. Z88 also could enhance the accumulation of rhodamine 123. Further studies showed that Z88 could inhibit the verapamil stimulated Pgp ATPase activity. Additionally, qPCR detection and western blot assays revealed that Z88 could decrease the expression of P-gp at both RNA and protein level.
Conclusion: Z88 exerted potent anti-MDR activity in vitro and its mechanisms are associated with dualinhibition of the function and expression of P-gp. These findings encourage efforts to develop more effective reversal agents to circumvent MDR based on Z88.
Export Options
About this article
Cite this article as:
Liu Zulong, Zhu Hengrui , Qu Shijin , Tang Lisha , Cao Lihuan , Yu Wenbo , Yang Xianmei , Jiang Songmin , Zhu Dayuan , Tan Changheng*, Yu Long *, Pyramidatine (Z88) Sensitizes Vincristine-Resistant Human Oral Cancer (KB/VCR) Cells to Chemotherapeutic Agents by Inhibition of P-glycoprotein, Anti-Cancer Agents in Medicinal Chemistry 2018; 18 (2) . https://dx.doi.org/10.2174/1871520617666170803155025
DOI https://dx.doi.org/10.2174/1871520617666170803155025 |
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 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 metastasis ...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 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
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
![](/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
-
Spectral Imaging Technology - A Review on Skin and Endoscopy Applications
Recent Patents on Medical Imaging ROS Modulate Cell Death Mechanism in Cervical Cancer Cells Treated with the Combination of Polyphenolic Compounds and Anticancer Drug Cisplatin: A Review
Current Cancer Therapy Reviews Neurotrophic and Neuroprotective Effects of Muscle Contraction
Current Pharmaceutical Design Effects of Polysaccharides from Selenium-enriched Pyracantha fortuneana on Mice Liver Injury
Medicinal Chemistry Bile Acid Nanoparticles - An Emerging Approach for Site Specific Drug Targeting
Current Nanomedicine Preparation and Biodistribution of Technetium-99m-Labeled Bis- Misonidazole (MISO) as an Imaging Agent for Tumour Hypoxia
Medicinal Chemistry The Association of Chemotherapy and Radiotherapy in Squamous Cell Carcinoma of Anal Canal
Current Drug Therapy The Role of Targeted HIV Screening in the Emergency Department: A Scoping Review
Current HIV Research Non-Celiac Gluten Sensitivity Triggers Gut Dysbiosis, Neuroinflammation, Gut-Brain Axis Dysfunction, and Vulnerability for Dementia
CNS & Neurological Disorders - Drug Targets Negative Regulation of NEDD8 Conjugation Pathway by Novel Molecules and Agents for Anticancer Therapy
Current Pharmaceutical Design Beta-glucans is a Potential Inhibitor of Ovarian Cancer: Based on Molecular and Biological Aspects
Current Pharmaceutical Biotechnology Vasculogenic and Angiogenic Pathways in Moyamoya Disease
Current Medicinal Chemistry Targeting Transcription Factors for Cancer Therapy
Current Pharmaceutical Design Targeting IAPs as An Approach to Anti-Cancer Therapy
Current Topics in Medicinal Chemistry The Nuclear Orphan Receptor NR4A1 and NR4A3 as Tumor Suppressors in Hematologic Neoplasms
Current Drug Targets Effective Prodrug Liposome and Conversion to Active Metabolite
Current Drug Metabolism Targeting Established Tumor Vasculature: A Novel Approach to Cancer Treatment
Current Cancer Therapy Reviews Stimuli-Responsive Nanoparticles for siRNA Delivery
Current Pharmaceutical Design Synthesis, Structure Activity Relationship (SAR), and Biological Activities of Benzylideneacetophenones Derivatives
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Renal Lesions with Low-level Enhancement on Contrast-enhanced CT Promotes Early Detection of Drug-induced Kidney Injury in Patients Administered Anticancer Drugs
Current Medical Imaging