Author:
Chung Jae Heun,Choi Ho Jung,Kang Yong Jung,Kim Yun Seong,Lee Sang-Yull,Kwon Ryuk Jun,Jeong Han-Sol,Park Su-Jung,Jeong Yeongmu,Kang Dongwan,Ko Jeongin,Noh SangGyun,Chung Hae Young,Moon Hyung Ryong,Yoon Seong Hoon
Abstract
Abstract
Background
The protein kinase A (PKA)/cAMP response element-binding protein (CREB) has been suggested to be related to the inhibition of the proliferation of non-small cell lung cancer (NSCLC) cells. This study aimed to investigate the efficacy of a novel diarylcyclohexanone derivative, MHY4571, in regulating the PKA-CREB pathway and to study its anti-tumor role in squamous NSCLC.
Methods
We designed MHY4571 as a novel PKA inhibitor with acceptable in silico ADME properties and tested it in vitro in lung cancer cell lines and in vivo in xenograft and orthotopic mouse models of squamous cell lung carcinoma.
Results
MHY4571 inhibited PKA activity (> 70% inhibition) and suppressed the expression of p-PKA and p-CREB dose-dependently. MHY4571 treatment reduced lung cancer cell viability and promoted caspase 3-dependent apoptotic cell death. Orally administered MHY4571 significantly suppressed lung tumor growth in xenograft and orthotopic mouse models. PKA catalytic subunit alpha-silencing by siRNA (siPKA) strongly attenuated CREB phosphorylation; siCREB did not alter PKA protein levels or its phosphorylation, suggesting that PKA is an upstream regulator of CREB activity. MHY4571 acted synergistically with cisplatin (on co-treatment) to induce apoptotic cell death in lung cancer cells.
Conclusions
Our results imply that MHY4571 may be a potential drug candidate for squamous cell lung cancer treatment.
Funder
National Research Foundation of Korea (NRF) grant, funded by the Korean government
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Hematology
Cited by
4 articles.
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