PloS one, 2015-06, Vol.10 (6), p.e0127841-e0127841
2015
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Suppression of MAPK Signaling and Reversal of mTOR-Dependent MDR1-Associated Multidrug Resistance by 21α-Methylmelianodiol in Lung Cancer Cells
- Ist Teil von
- PloS one, 2015-06, Vol.10 (6), p.e0127841-e0127841
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Lung cancer is the leading cause of cancer-related deaths worldwide and remains the most prevalent. Interplay between PI3K/AMPK/AKT and MAPK pathways is a crucial effector in lung cancer growth and progression. These signals transduction protein kinases serve as good therapeutic targets for non-small cell lung cancer (NSCLC) which comprises up to 90% of lung cancers. Here, we described whether 21α-Methylmelianodiol (21α-MMD), an active triterpenoid derivative of Poncirus trifoliate, can display anticancer properties by regulating these signals and modulate the occurrence of multidrug resistance in NSCLC cells. We found that 21α-MMD inhibited the growth and colony formation of lung cancer cells without affecting the normal lung cell phenotype. 21α-MMD also abrogated the metastatic activity of lung cancer cells through the inhibition of cell migration and invasion, and induced G0/G1 cell cycle arrest with increased intracellular ROS generation and loss of mitochondrial membrane integrity. 21α-MMD regulated the expressions of PI3K/AKT/AMPK and MAPK signaling which drove us to further evaluate its activity on multidrug resistance (MDR) in lung cancer cells by specifying on P-glycoprotein (P-gp)/MDR1-association. Employing the established paclitaxel-resistant A549 cells (A549-PacR), we further found that 21α-MMD induced a MDR reversal activity through the inhibition of P-gp/MDR1 expressions, function, and transcription with regained paclitaxel sensitivity which might dependently correlate to the regulation of PI3K/mTOR signaling pathway. Taken together, these findings demonstrate, for the first time, the mechanistic evaluation in vitro of 21α-MMD displaying growth-inhibiting potential with influence on MDR reversal in human lung cancer cells.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0127841Titel-ID: cdi_plos_journals_1690399876
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, AKT protein, AMP-Activated Protein Kinases - metabolism, Anticancer properties, Antineoplastic Agents - pharmacology, ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism, Autophagy, Cancer, Cancer therapies, Carcinoma, Non-Small-Cell Lung - drug therapy, Cell cycle, Cell growth, Cell Line, Tumor, Cell migration, Cell Movement - drug effects, Cell Proliferation - drug effects, Colorectal cancer, Drug Combinations, Drug Resistance, Multiple - drug effects, Drug Resistance, Neoplasm - drug effects, Drugs, G1 Phase Cell Cycle Checkpoints - drug effects, Gastric cancer, Glycoproteins, Humans, Inhibition, Kinases, Liver cancer, Lung cancer, Lung diseases, Lung Neoplasms - drug therapy, Lymphoma, Lymphomas, MAP kinase, MAP Kinase Signaling System - drug effects, MDR1 protein, Medical prognosis, Membrane Potential, Mitochondrial - drug effects, Metastases, Metastasis, Mitochondria, Multidrug resistance, Multidrug resistant organisms, Natural products, Neoplasm Invasiveness - pathology, Non-small cell lung carcinoma, P-Glycoprotein, Paclitaxel, Paclitaxel - pharmacology, Pharmacy, Phenotypes, Phosphatidylinositol 3-Kinases - metabolism, Poncirus trifoliata, Proto-Oncogene Proteins c-akt - metabolism, Reactive Oxygen Species - metabolism, RNA Interference, RNA, Small Interfering, Signal transduction, Signaling, Stomach cancer, Therapeutic applications, TOR protein, TOR Serine-Threonine Kinases - metabolism, Transcription, Triterpenes - pharmacology