Acetyl-macrocalin B, anent-kaurane diterpenoid, initiates apoptosis through the ROS-p38-caspase 9-dependent pathway and induces G2/M phase arrest via the Chk1/2-Cdc25C-Cdc2/cyclin B axis in non-small cell lung cancer
Autor: | Zhirong Zhang, Jie He, Ning Li, Nan Sun, Yun Che, Jun Wan, Han-Dong Sun, Jing Nan Wang, Yuan Li, Zhiliang Lu, Zu Yang Yuan, Pema Tenzin Puno |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cancer Research Lung Neoplasms Cyclin B Mice Nude Apoptosis Cell Cycle Proteins Thiophenes Mitogen-Activated Protein Kinase 14 Mice 03 medical and health sciences 0302 clinical medicine Nude mouse Carcinoma Non-Small-Cell Lung Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Animals Humans Urea Cyclin B1 Caspase Pharmacology A549 cell Cyclin-dependent kinase 1 Lamiaceae biology Chemistry Drug Synergism Cell cycle biology.organism_classification Xenograft Model Antitumor Assays Caspase 9 G2 Phase Cell Cycle Checkpoints 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Molecular Medicine Female Diterpenes Reactive Oxygen Species Signal Transduction Research Paper |
Zdroj: | Cancer Biology & Therapy. 19:609-621 |
ISSN: | 1555-8576 1538-4047 |
Popis: | Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, and novel effective drugs against NSCLC are urgently needed. Isodon species are rich in ent-kaurane diterpenoids that have been reported to have antitumor bioactivity. Acetyl-macrocalin B (A-macB) is a novel ent-kaurane diterpenoid isolated from Isodon silvatica, and its antitumor efficacy against NSCLC and the underlying mechanisms were scrutinized in depth. The viability of cells treated with A-macB was detected by CCK-8 and colony formation assays. Apoptosis and cell cycle distribution were analyzed by flow cytometry. The mechanisms were investigated by detecting ROS and performing western blotting and verification experiments with specific inhibitors. The in vivo effect of A-macB was explored in a nude mouse xenograft model. A-macB effectively inhibited H1299 and A549 cell viability, triggered apoptosis and delayed cells in the G2/M phase. A-macB induced cellular ROS production and then activated the p38 MAPK-mediated, caspase 9-dependent apoptotic pathway. Both the ROS scavenger NAC and the specific p38 inhibitor SB203580 inactivated the function of p38 induced by A-macB, thus preventing cells from apoptosis. A-macB activated the Chk1/2-Cdc25C-Cdc2/cyclin B1 axis to induce G2/M phase arrest. AZD7762 abrogated the function of Chk1/2, abolished the G2/M delay and enhanced the cytotoxicity of A-macB. Moreover, A-macB efficiently suppressed tumor growth in a mouse xenograft model without noticeable toxicity to normal tissues. Having both efficacy and relative safety, A-macB is a potential lead compound that is worthy of further exploration for development as an anticancer agent. |
Databáze: | OpenAIRE |
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