Nootkatone, an AMPK activator derived from grapefruit, inhibits KRAS downstream pathway and sensitizes non-small-cell lung cancer A549 cells to adriamycin
| Autor: | Jeong Yong Moon, Le Van Manh Hung, Ji-yeon Ryu, Somi Kim Cho |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
MAPK/ERK pathway
Male Lung Neoplasms Pharmaceutical Science Mice Nude AMP-Activated Protein Kinases Proto-Oncogene Proteins p21(ras) 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Drug Discovery Antineoplastic Combined Chemotherapy Protocols Cytotoxic T cell Animals Humans Viability assay Protein kinase B 030304 developmental biology Cell Proliferation Pharmacology A549 cell Polycyclic Sesquiterpenes 0303 health sciences Mice Inbred BALB C Cell growth Chemistry Cell Cycle AMPK Cell cycle Xenograft Model Antitumor Assays Metformin Complementary and alternative medicine A549 Cells Doxorubicin Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Molecular Medicine Citrus paradisi |
| Zdroj: | Phytomedicine : international journal of phytotherapy and phytopharmacology. 63 |
| ISSN: | 1618-095X |
| Popis: | Background Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and it is intrinsically resistant to anticancer drugs. Nootkatone (NKT), which is the main fragrant component of grapefruit, has been identified as a bioactive compound with a wide range of beneficial applications. NKT can activate AMP-activated protein kinase (AMPK) in liver and muscle cells, however, little is known about the role of NKT in cancer, particularly its role in NSCLC with high rates of liver kinase B1 (LKB1) and KRAS mutations. Purpose The anti-cancer activities of NKT in NSCLC A549 cells and ADR-resistant A549/ADR cells were investigated and compared to those of metformin, an AMPK activator that is used clinically as an AMPK activator. Methods Cell viability, proliferation and NKT sensitization were determined by the MTT assay. Mechanisms of NKT against anti-cancer activities including AMPK activation, cell cycle arrest, and synergistic cytotoxic effect were evaluated by Western blot analysis, and flow cytometry. In in vivo experiments, athymic BALB/c male nude mice were used for experiments. After the successful generation of tumor models through subcutaneous injection of A549/ADR cells, NKT and/or ADR were administered and mice were kept for weekly measurements for up to 7 weeks. The animals were then sacrificed, and the tumors were removed from all animals and weighed. Results NKT activated AMPK via LKB1-independent and CAMKK2-dependent pathways, leading to inhibition of cell growth and induction of G1 cell arrest. The effect of NKT is comparable but superior to that of metformin, an AMPK activator in clinical use. Importantly, NKT inhibited the activation of oncogenic AKT and ERK proteins, while metformin inhibited AKT but failed to impact ERK, the major oncogenic protein of NSCLC cells with KRAS mutation. The synergistic activity of NKT and ADR was more effective than that of metformin and ADR. In vivo data confirmed synergistic effects of NKT and ADR without systemic side effects. Conclusion We demonstrate for the first time that NKT can sensitize ADR-resistant A549/ADR cells to ADR in vitro and in vivo. Metformin, on the other hand, failed to show any synergistic effect with ADR in A549/ADR cells. |
| Databáze: | OpenAIRE |
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