Anticancer effect of propranolol on diethylnitrosamine-induced hepatocellular carcinoma rat model

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY Fundamental & Clinical Pharmacology Pub Date : 2024-02-07 DOI:10.1111/fcp.12990

Yomna M. Tamim, Ahmed A. Nagy, Ahmed M. Abdellah, Ahmed H. Osman, Amel F. M. Ismail

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Abstract

Background

Hepatocellular carcinoma (HCC) is the most widespread type of primary liver cancer. Diethylnitrosamine (DEN), a hepatotoxic hepatocarcinogenic compound, is used to induce HCC in animal models. The non-selective β-blocker propranolol demonstrated antiproliferative activity in many cancer types.

Objective

This investigation aimed to evaluate the anticancer effect of propranolol against DEN-induced HCC in rats.

Methods

Thirty adult male rats were divided into the following groups: Group I (C, control), Group II (HCC); received DEN, 70 mg/kg body weight (b.wt.) once a week for 10 weeks, to induce HCC, and Group III (HCC/Prop); received DEN for 10 weeks for HCC induction, then received 20 mg/kg b.wt. propranolol, intraperitoneally for four successive weeks.

Results

HCC was developed in rats' livers and confirmed via significant liver architecture changes, significantly elevated activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), α-fetoprotein (AFP), total- and direct-bilirubin (Bil), and a decline in albumin (ALB) level in serum. HCC group demonstrated elevated levels of malondialdehyde (MDA), nitric oxide (NO), HIF-1α, IL-8, NF-κB, PGE2, TGF-β1, VEGF, and CD8, but significant decline of GSH, and IL-10 level, with suppression of the antioxidant enzymes' activities. In addition, the gene expression of the hepatic inducible nitric oxide synthase (iNOS), and LAG-3 were up-regulated. Moreover, the protein expression of p-PKC was up-regulated, while that of PD-1 and PD-L1 were down-regulated in the liver tissues of the HCC group. However, propranolol ameliorated the investigated parameters in the HCC/Prop group.

Conclusion

Propranolol exhibited an anticancer effect and thus can be considered as a promising treatment for HCC. Blocking of PD-1/PD-L1 and LAG-3 signals participated in the anti-tumor effect of propranolol on HCC.

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普萘洛尔对二乙基亚硝胺诱导的肝细胞癌大鼠模型的抗癌作用

背景：肝细胞癌（HCC）是最常见的原发性肝癌类型。二乙基亚硝胺（DEN）是一种具有肝毒性的致肝癌化合物，可用于诱导动物模型中的 HCC。非选择性β-受体阻滞剂普萘洛尔在许多癌症类型中都具有抗增殖活性：本研究旨在评估普萘洛尔对 DEN 诱导的大鼠 HCC 的抗癌作用：方法：将 30 只成年雄性大鼠分为以下几组：方法：将30只成年雄性大鼠分为以下几组：I组（C，对照组）；II组（HCC组）；接受DEN诱导HCC，每周一次，每次70 mg/kg体重，共10周；III组（HCC/普萘洛尔组）；接受DEN诱导HCC，共10周，然后腹腔注射20 mg/kg体重的普萘洛尔，连续4周：结果：大鼠肝脏发生了 HCC，并通过肝脏结构的显著变化、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、α-胎儿蛋白（AFP）、总胆红素和直接胆红素（Bil）活性的显著升高以及血清中白蛋白（ALB）水平的下降证实了这一点。HCC 组的丙二醛（MDA）、一氧化氮（NO）、HIF-1α、IL-8、NF-κB、PGE2、TGF-β1、VEGF 和 CD8 水平升高，但 GSH 和 IL-10 水平显著下降，抗氧化酶活性受到抑制。此外，肝脏诱导型一氧化氮合酶（iNOS）和 LAG-3 的基因表达上调。此外，HCC 组肝脏组织中 p-PKC 蛋白表达上调，而 PD-1 和 PD-L1 蛋白表达下调。然而，普萘洛尔能改善HCC/Prop组的相关指标：结论：普萘洛尔具有抗癌作用，因此可被视为一种治疗 HCC 的有效方法。阻断 PD-1/PD-L1 和 LAG-3 信号参与了普萘洛尔对 HCC 的抗肿瘤作用。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.