The PI3Kα inhibitor DFX24 suppresses tumor growth and metastasis in non-small cell lung cancer via ERK inhibition and EPHB6 reactivation.

Abstract

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.

• Authors: Yan-Hua Fan, Huai-Wei Ding, Donghwa Kim, Jian-Yu Liu, Ji-Young Hong, Yong-Nan Xu, Daoping Wang, Xiao-Sheng Yang, Sang Kook Lee
• Journal: Pharmacological research (Pharmacol Res) Vol. 160 Pg. 105147 (10 2020) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 32814167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020. Published by Elsevier Ltd.

Chemical References

• Antineoplastic Agents
• Benzene Derivatives
• DFX24
• Morpholines
• Protein Kinase Inhibitors
• Pyridines
• Quinazolines
• Sulfonamides
• EPHB6 protein, human
• Receptors, Eph Family
• Oncogene Protein v-akt

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzene Derivatives (pharmacology)
• Carcinoma, Non-Small-Cell Lung (prevention & control)
• Cell Cycle Checkpoints (drug effects)
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Lung Neoplasms (prevention & control)
• MAP Kinase Signaling System (drug effects)
• Mitochondria (drug effects, metabolism)
• Morpholines (pharmacology)
• Neoplasm Metastasis (prevention & control)
• Oncogene Protein v-akt (drug effects)
• Phosphatidylinositol 3-Kinases (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (pharmacology)
• Quinazolines (pharmacology)
• Receptors, Eph Family (drug effects, metabolism)
• Sulfonamides (pharmacology)
• Xenograft Model Antitumor Assays