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Rho-kinase inhibition by Fasudil promotes tumor maturation and apoptosis in small-cell lung cancer.

ABSTRACT: Small-cell lung cancer (SCLC) is a poorly differentiated neuroendocrine neoplasm with inadequate therapeutic options. Fasudil is a Rho-associated protein kinase 1 and 2 (ROCK1/2) inhibitor whose clinical indications remain limited in cardiocerebrovascular diseases. This study aimed to report a possible implication of Fasudil for SCLC. The expression and prognostic value of ROCK1/2 were investigated immunohistochemically in surgical specimens. The positive rates of ROCK1 (77/113, 68.1%) and ROCK2 (94/113, 83.2%) were distinctly higher in SCLC than in other lung neuroendocrine tumors. The high expression level of ROCK1 was related to the poor long-term survival of patients, especially in the classic SCLC subtype. In vitro, SCLC cell line treated with Fasudil exhibited synapse-like morphologic change, accompanied by a reduction in the expression levels of c-myc and cyclin D1. Cell cycle arrest was further demonstrated, accompanied by sensitivity to starvation-induced apoptosis, indicating tumor maturation. In addition, RNA-seq identified hundreds of differentially expressed genes involved in the positive regulation of neuron differentiation, stem cell differentiation, cell development, and nervous system development. Finally, Fasudil inhibited SCLC growth, promoted structural maturity, and induced apoptosis in BALB/c nude mice xenograft model. In conclusion, these results indicated a potential and novel application of Fasudil for SCLC treatment.

SUBMITTER: Huo Z

PROVIDER: S-EPMC7476155 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Rho-kinase inhibition by Fasudil promotes tumor maturation and apoptosis in small-cell lung cancer.

Huo Zitian Z Su Yinxia Y Dong Yuting Y Zheng Yiyun Y Zhang Qian Q Duan Yaqi Y Wang Guoping G

American journal of translational research 20200815 8

Small-cell lung cancer (SCLC) is a poorly differentiated neuroendocrine neoplasm with inadequate therapeutic options. Fasudil is a Rho-associated protein kinase 1 and 2 (ROCK1/2) inhibitor whose clinical indications remain limited in cardiocerebrovascular diseases. This study aimed to report a possible implication of Fasudil for SCLC. The expression and prognostic value of ROCK1/2 were investigated immunohistochemically in surgical specimens. The positive rates of ROCK1 (77/113, 68.1%) and ROCK2 ...[more]

PMID: 32913511

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Project description:Background: Fasudil, a Rho kinase inhibitor, exerts therapeutic effects in a mouse model of Alzheimer's disease (AD), a chronic neurodegenerative disease with progressive loss of memory. However, the mechanisms remain unclear. In addition, the gut microbiota and its metabolites have been implicated in AD. Methods: We examined the effect of fasudil on learning and memory using the Morris water-maze (MWM) test in APPswe/PSEN1dE9 transgenic (APP/PS1) mice (8 months old) treated (i.p.) with fasudil (25 mg/kg/day; ADF) or saline (ADNS) and in age- and gender-matched wild-type (WT) mice. Fecal metagenomics and metabolites were performed to identify novel biomarkers of AD and elucidate the mechanisms of fasudil induced beneficial effects in AD mice. Results: The MWM test showed significant improvement of spatial memory in APP/PS1 mice treated with fasudil as compared to ADNS. The metagenomic analysis revealed the abundance of the dominant phyla in all the three groups, including Bacteroidetes (23.7-44%) and Firmicutes (6.4-26.6%), and the increased relative abundance ratio of Firmicutes/Bacteroidetes in ADNS (59.1%) compared to WT (31.7%). In contrast, the Firmicutes/Bacteroidetes ratio was decreased to the WT level in ADF (32.8%). Lefse analysis of metagenomics identified s_Prevotella_sp_CAG873 as an ADF potential biomarker, while s_Helicobacter_typhlonius and s_Helicobacter_sp_MIT_03-1616 as ADNS potential biomarkers. Metabolite analysis revealed the increment of various metabolites, including glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotriene, which were relative to ADNS or ADF microbiota potential biomarkers and mainly involved in the metabolism of nucleotide, lipids and sugars, and the inflammatory pathway. Conclusions: Memory deficit in APP/PS1 mice was correlated with the gut microbiome and metabolite status. Fasudil reversed the abnormal gut microbiota and subsequently regulated the related metabolisms to normal in the AD mice. It is believed that fasudil can be a novel strategy for the treatment of AD via remodeling of the gut microbiota and metabolites. The novel results also provide valuable references for the use of gut microbiota and metabolites as diagnostic biomarkers and/or therapeutic targets in clinical studies of AD.

Dataset Information

Rho-kinase inhibition by Fasudil promotes tumor maturation and apoptosis in small-cell lung cancer.

Publications

Rho-kinase inhibition by Fasudil promotes tumor maturation and apoptosis in small-cell lung cancer.

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