Nalidixic acid potentiates the antitumor activity in sorafenib-resistant hepatocellular carcinoma via the tumor immune microenvironment analysis

Zhi-Yong Liu; Zhi-Yong Liu; Dan-Ying Zhang; Dan-Ying Zhang; Xia-Hui Lin; Xia-Hui Lin; Jia-Lei Sun; Jia-Lei Sun; Weinire Abuduwaili; Weinire Abuduwaili; Guang-Cong Zhang; Guang-Cong Zhang; Ru-Chen Xu; Ru-Chen Xu; Fu Wang; Fu Wang; Xiang-Nan Yu; Xiang-Nan Yu; Xuan Shi; Xuan Shi; Bin Deng; Ling Dong; Ling Dong; Shu-Qiang Weng; Shu-Qiang Weng; Ji-Min Zhu; Ji-Min Zhu; Xi-Zhong Shen; Xi-Zhong Shen; Xi-Zhong Shen; Tao-Tao Liu; Tao-Tao Liu

doi:10.3389/fphar.2022.952482

Frontiers in Pharmacology (Aug 2022)

Nalidixic acid potentiates the antitumor activity in sorafenib-resistant hepatocellular carcinoma via the tumor immune microenvironment analysis

Zhi-Yong Liu,
Zhi-Yong Liu,
Dan-Ying Zhang,
Dan-Ying Zhang,
Xia-Hui Lin,
Xia-Hui Lin,
Jia-Lei Sun,
Jia-Lei Sun,
Weinire Abuduwaili,
Weinire Abuduwaili,
Guang-Cong Zhang,
Guang-Cong Zhang,
Ru-Chen Xu,
Ru-Chen Xu,
Fu Wang,
Fu Wang,
Xiang-Nan Yu,
Xiang-Nan Yu,
Xuan Shi,
Xuan Shi,
Bin Deng,
Ling Dong,
Ling Dong,
Shu-Qiang Weng,
Shu-Qiang Weng,
Ji-Min Zhu,
Ji-Min Zhu,
Xi-Zhong Shen,
Xi-Zhong Shen,
Xi-Zhong Shen,
Tao-Tao Liu,
Tao-Tao Liu

Affiliations

Zhi-Yong Liu: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Zhi-Yong Liu: Shanghai Institute of Liver Disease, Shanghai, China
Dan-Ying Zhang: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Dan-Ying Zhang: Shanghai Institute of Liver Disease, Shanghai, China
Xia-Hui Lin: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Xia-Hui Lin: Shanghai Institute of Liver Disease, Shanghai, China
Jia-Lei Sun: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Jia-Lei Sun: Shanghai Institute of Liver Disease, Shanghai, China
Weinire Abuduwaili: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Weinire Abuduwaili: Shanghai Institute of Liver Disease, Shanghai, China
Guang-Cong Zhang: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Guang-Cong Zhang: Shanghai Institute of Liver Disease, Shanghai, China
Ru-Chen Xu: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Ru-Chen Xu: Shanghai Institute of Liver Disease, Shanghai, China
Fu Wang: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Fu Wang: Shanghai Institute of Liver Disease, Shanghai, China
Xiang-Nan Yu: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Xiang-Nan Yu: Shanghai Institute of Liver Disease, Shanghai, China
Xuan Shi: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Xuan Shi: Shanghai Institute of Liver Disease, Shanghai, China
Bin Deng: Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou, China
Ling Dong: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Ling Dong: Shanghai Institute of Liver Disease, Shanghai, China
Shu-Qiang Weng: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Shu-Qiang Weng: Shanghai Institute of Liver Disease, Shanghai, China
Ji-Min Zhu: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Ji-Min Zhu: Shanghai Institute of Liver Disease, Shanghai, China
Xi-Zhong Shen: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Xi-Zhong Shen: Shanghai Institute of Liver Disease, Shanghai, China
Xi-Zhong Shen: Key Laboratory of Medical Molecular Virology, Shanghai Medical College of Fudan University, Shanghai, China
Tao-Tao Liu: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
Tao-Tao Liu: Shanghai Institute of Liver Disease, Shanghai, China

DOI: https://doi.org/10.3389/fphar.2022.952482
Journal volume & issue: Vol. 13

Abstract

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Sorafenib resistance is often developed and impedes the benefits of clinical therapy in hepatocellular carcinoma (HCC) patients. However, the relationship between sorafenib resistance and tumor immune environment and adjuvant drugs for sorafenib-resistant HCC are not systemically identified. This study first analyzed the expression profiles of sorafenib-resistant HCC cells to explore immune cell infiltration levels and differentially expressed immune-related genes (DEIRGs). The prognostic value of DEIRGs was analyzed using Cox regression and Kaplan–Meier analysis based on The Cancer Genome Atlas. The primary immune cells infiltrated in sorafenib-resistant HCC mice were explored using flow cytometry (FCM). Finally, small-molecule drugs for sorafenib-resistant HCC treatment were screened and validated by experiments. The CIBERSORT algorithm and mice model showed that macrophages and neutrophils are highly infiltrated, while CD8+ T cells are downregulated in sorafenib-resistant HCC. Totally, 34 DEIRGs were obtained from sorafenib-resistant and control groups, which were highly enriched in immune-associated biological processes and pathways. NR6A1, CXCL5, C3, and TGFB1 were further identified as prognostic markers for HCC patients. Finally, nalidixic acid was identified as a promising antagonist for sorafenib-resistant HCC treatment. Collectively, our study reveals the tumor immune microenvironment changes and explores a promising adjuvant drug to overcome sorafenib resistance in HCC.

Published in Frontiers in Pharmacology

ISSN: 1663-9812 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://journal.frontiersin.org/journals/pharmacology

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