二肽基肽酶-4酶抑制作用及其对肝脏癌前病变的影响：肝癌治疗的新途径。

Dipeptidyl peptidase-4 enzyme inhibition and its impacts on hepatic preneoplasia: a new avenue for liver cancer management.

作者信息

Eitah Hebatollah E, Sayed Rabab H, Maklad Yousreya A, Gamal El Din Amina A, Mahmoud Khaled, El-Sahar Ayman E, Alhejely Amani, Abdulbaqi Amal A, Naeim Attia Hanan

机构信息

Medicinal and Pharmaceutical Chemistry Department, (Pharmacology Group), National Research Centre, Giza, Egypt.

Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

出版信息

Front Pharmacol. 2025 Jul 25;16:1559303. doi: 10.3389/fphar.2025.1559303. eCollection 2025.

DOI:10.3389/fphar.2025.1559303

PMID:40786041

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12331699/

Abstract

AIMS

Dipeptidyl peptidase-4 enzyme (DPP-4) was reported to be associated with immune stimulation, resistance to anti-neoplastic agents and lipid accumulation. Dysregulated DPP-4 expression was reported in various malignant tumors such as hepatocellular carcinoma. Hence, the influence of sitagliptin, an inhibitor of DPP-4 enzyme, was performed (HepG2 cells) and (mouse model of hepatic preneoplasia).

MAIN METHODS

The effect of sitagliptin was investigated MTT assay. The model of hepatic preneoplasia was conducted by weekly intraperitoneal injection of 75 mg/kg of diethylnitrosamine (DEN) for five successive weeks. Mice were treated daily with sitagliptin (50 mg/kg, p.o.) starting 1 week after DEN injection till the end of the experiment.

KEY FINDINGS

Sitagliptin exerted a significant cytotoxic effect on HepG2 cells, which was dependent on elevating mRNA expression of p53 and BAX/BCL2. Sitagliptin also improved serum liver enzymes and attenuated histopathological alterations in mice. These changes were accompanied by reducing liver GGT, DPP-4, CYP2E1, GGT-P, NF-κB and PCNA along with increasing CYP3A4. Furthermore, sitagliptin attenuated DEN-induced liver DNA damage and inflammation.

SIGNIFICANCE

These findings shed the light on the role of DPP-inhibitors in the future of cancer therapy and management.

摘要

目的

据报道，二肽基肽酶-4（DPP-4）与免疫刺激、抗肿瘤药物耐药性和脂质积累有关。在各种恶性肿瘤如肝细胞癌中，已报道DPP-4表达失调。因此，研究了DPP-4酶抑制剂西他列汀对（HepG2细胞）和（肝前病变小鼠模型）的影响。

主要方法

通过MTT法研究西他列汀的作用。肝前病变模型通过连续5周每周腹腔注射75mg/kg二乙基亚硝胺（DEN）建立。在注射DEN后1周开始，小鼠每天口服西他列汀（50mg/kg）直至实验结束。

主要发现

西他列汀对HepG2细胞具有显著的细胞毒性作用，这取决于p53和BAX/BCL2 mRNA表达的升高。西他列汀还改善了小鼠血清肝酶水平并减轻了组织病理学改变。这些变化伴随着肝脏γ-谷氨酰转移酶（GGT）、DPP-4、细胞色素P450 2E1（CYP2E1）、GGT-P、核因子κB（NF-κB）和增殖细胞核抗原（PCNA）的减少以及细胞色素P450 3A4（CYP3A4）的增加。此外，西他列汀减轻了DEN诱导的肝脏DNA损伤和炎症。