MHY4571, a novel diarylcyclohexanone derivative, exerts anti-cancer activity by regulating the PKA-cAMP-response element-binding protein pathway in squamous cell lung cancer

Autor:	Jae Heun Chung, Ho Jung Choi, Yong Jung Kang, Yun Seong Kim, Sang-Yull Lee, Ryuk Jun Kwon, Han-Sol Jeong, Su-Jung Park, Yeongmu Jeong, Dongwan Kang, Jeongin Ko, SangGyun Noh, Hae Young Chung, Hyung Ryong Moon, Seong Hoon Yoon
Jazyk:	angličtina
Rok vydání:	2022
Předmět:	Lung cancer MHY4571 Carcinogenesis Cyclic AMP-Dependent Protein Kinases cAMP response element-binding protein Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Zdroj:	Experimental Hematology & Oncology, Vol 11, Iss 1, Pp 1-12 (2022)
Druh dokumentu:	article
ISSN:	2162-3619
DOI:	10.1186/s40164-022-00324-8
Popis:	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.
Databáze:	Directory of Open Access Journals
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