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A Marine Alkaloid, Ascomylactam A, Suppresses Lung Tumorigenesis via Inducing Cell Cycle G1/S Arrest through ROS/Akt/Rb Pathway.
- Source :
-
Marine drugs [Mar Drugs] 2020 Sep 27; Vol. 18 (10). Date of Electronic Publication: 2020 Sep 27. - Publication Year :
- 2020
-
Abstract
- Ascomylactam A was reported for the first time as a new 13-membered-ring macrocyclic alkaloid in 2019 from the mangrove endophytic fungus Didymella sp. CYSK-4 from the South China Sea. The aim of our study was to delineate the effects of ascomylactam A (AsA) on lung cancer cells and explore the antitumor molecular mechanisms underlying of AsA. In vitro, AsA markedly inhibited the cell proliferation with half-maximal inhibitory concentration (IC <subscript>50</subscript> ) values from 4 to 8 μM on six lung cancer cell lines, respectively. In vivo, AsA suppressed the tumor growth of A549, NCI-H460 and NCI-H1975 xenografts significantly in mice. Furthermore, by analyses of the soft agar colony formation, 5-ethynyl-20-deoxyuridine (EdU) assay, reactive oxygen species (ROS) imaging, flow cytometry and Western blotting, AsA demonstrated the ability to induce cell cycle arrest in G1 and G1/S phases by increasing ROS generation and decreasing of Akt activity. Conversely, ROS inhibitors and overexpression of Akt could decrease cell growth inhibition and cell cycle arrest induced by AsA. Therefore, we believe that AsA blocks the cell cycle via an ROS-dependent Akt/Cyclin D1/Rb signaling pathway, which consequently leads to the observed antitumor effect both in vitro and in vivo. Our results suggest a novel leading compound for antitumor drug development.
- Subjects :
- Alkaloids administration & dosage
Alkaloids isolation & purification
Animals
Antineoplastic Agents administration & dosage
Antineoplastic Agents isolation & purification
Cell Line, Tumor
Cell Proliferation drug effects
G1 Phase Cell Cycle Checkpoints drug effects
Humans
Inhibitory Concentration 50
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Proto-Oncogene Proteins c-akt metabolism
Reactive Oxygen Species metabolism
Retinoblastoma Protein metabolism
S Phase Cell Cycle Checkpoints drug effects
Signal Transduction drug effects
Xenograft Model Antitumor Assays
Alkaloids pharmacology
Antineoplastic Agents pharmacology
Ascomycota chemistry
Lung Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1660-3397
- Volume :
- 18
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Marine drugs
- Publication Type :
- Academic Journal
- Accession number :
- 32992455
- Full Text :
- https://doi.org/10.3390/md18100494