The PI3Kα inhibitor DFX24 suppresses tumor growth and metastasis in non-small cell lung cancer via ERK inhibition and EPHB6 reactivation
Autor: | Jianyu Liu, Xiao-Sheng Yang, Ji-Young Hong, Sang Kook Lee, Donghwa Kim, Daoping Wang, Yongnan Xu, Huai-Wei Ding, Yanhua Fan |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
MAPK/ERK pathway Cell cycle checkpoint Lung Neoplasms Cell Survival MAP Kinase Signaling System Pyridines Morpholines non-small cell lung cancer (NSCLC) Antineoplastic Agents Apoptosis Metastasis 03 medical and health sciences Phosphatidylinositol 3-Kinases 0302 clinical medicine Cell Movement Carcinoma Non-Small-Cell Lung medicine Benzene Derivatives Humans Neoplasm Metastasis Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Receptors Eph Family Pharmacology Sulfonamides Chemistry Cell growth Cell Cycle Checkpoints medicine.disease Xenograft Model Antitumor Assays Mitochondria Oncogene Protein v-akt 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell Cancer research Quinazolines Drug Screening Assays Antitumor |
Zdroj: | Pharmacological research. 160 |
ISSN: | 1096-1186 |
Popis: | EPHB6 is a metastasis inhibitory gene that is frequently decreased or deficiency in non-small cell lung cancer (NSCLC), which contributed to the subsequent development of distant metastasis. These suggested the possibility that reactivation of EPHB6 might prevent the metastasis of NSCLC. Nevertheless, EPHB6 expression might also promote cancer cell growth and inhibit cell apoptosis by activating Akt and ERK pathway, apart from inhibition of migration and invasion. In the present study, we developed a novel quinazolin-4(3H)-one analog (DFX24) as a potential PI3Kα inhibitor, which inhibited both cell proliferation and metastasis of NSCLC cell lines. Investigation to the molecular mechanisms revealed DFX24 inhibited the cell growth and metastasis via inhibition of PI3Kα and ERK activity, as well as the increase in EPHB6 expression. In addition, DFX24 also induced cell cycle arrest and tumor cell apoptosis by inhibiting PI3K/Akt pathway and activating mitochondria-dependent pathway, respectively. These findings suggested that DFX24 might be considered as a novel drug candidate and may provide a potential therapy for NSCLC. |
Databáze: | OpenAIRE |
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