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Dual Inhibition of Topoisomerase II and Tyrosine Kinases by the Novel Bis-Fluoroquinolone Chalcone-Like Derivative HMNE3 in Human Pancreatic Cancer Cells
- Source :
- PLoS ONE, PLoS ONE, Vol 11, Iss 10, p e0162821 (2016)
- Publication Year :
- 2016
- Publisher :
- Public Library of Science (PLoS), 2016.
-
Abstract
- Both tyrosine kinase and topoisomerase II (TopII) are important anticancer targets, and their respective inhibitors are widely used in cancer therapy. However, some combinations of anticancer drugs could exhibit mutually antagonistic actions and drug resistance, which further limit their therapeutic efficacy. Here, we report that HMNE3, a novel bis-fluoroquinolone chalcone-like derivative that targets both tyrosine kinase and TopII, induces tumor cell proliferation and growth inhibition. The viabilities of 6 different cancer cell lines treated with a range of HMNE3 doses were detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cellular apoptosis was determined using Hoechst 33258 fluorescence staining and the terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay. The expression of activated Caspase-3 was examined by immunocytochemistry. The tyrosine kinase activity was measured with a human receptor tyrosine kinase (RTK) detection kit using a horseradish peroxidase (HRP)-conjugated phosphotyrosine (pY20) antibody as the substrate. The topoisomerase II activity was measured using agarose gel electrophoresis with the DNA plasmid pBR322 as the substrate. The expression levels of the P53, Bax, Bcl-2, Caspase-3, -8, -9, p-cSrc, c-Src and topoisomerase II proteins were detected by western blot analysis. The proliferation of five of the six cancer cell lines was significantly inhibited by HMNE3 at 0.312 to 10 μmol/L in a time- and dose-dependent manner. Treatment of the Capan-1 and Panc-1 cells with 1.6 to 3.2 μM HMNE3 for 48 h significantly increased the percentage of apoptotic cells (P
- Subjects :
- 0301 basic medicine
Cancer Treatment
lcsh:Medicine
DNA electrophoresis
Apoptosis
Biochemistry
Tyrosine Kinases
Receptor tyrosine kinase
chemistry.chemical_compound
Fluorescence Microscopy
Chalcone
0302 clinical medicine
Ciprofloxacin
Medicine and Health Sciences
Topoisomerase II Inhibitors
lcsh:Science
Gel Electrophoresis
Staining
Microscopy
Multidisciplinary
TUNEL assay
Cell Death
medicine.diagnostic_test
biology
Cell Staining
Light Microscopy
Protein-Tyrosine Kinases
Enzymes
Nucleic acids
Oncology
Cell Processes
030220 oncology & carcinogenesis
Growth inhibition
Tyrosine kinase
Research Article
Agarose Gel Electrophoresis
Research and Analysis Methods
Electrophoretic Techniques
Pancreatic Cancer
03 medical and health sciences
Western blot
Cell Line, Tumor
Gastrointestinal Tumors
Genetics
medicine
Humans
Protein Kinase Inhibitors
Topoisomerase
lcsh:R
Biology and Life Sciences
Proteins
Cancers and Neoplasms
Cell Biology
DNA
Cell Cycle Checkpoints
Molecular biology
Pancreatic Neoplasms
DNA Topoisomerases, Type II
030104 developmental biology
Terminal deoxynucleotidyl transferase
chemistry
Specimen Preparation and Treatment
Cell culture
Enzymology
biology.protein
lcsh:Q
Protein Kinases
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- PLOS ONE
- Accession number :
- edsair.doi.dedup.....5e7d7e8b9c38f36560b9de057b63adf1