Pantoprazole suppresses carcinogenesis and growth of hepatocellular carcinoma by inhibiting glycolysis and Na+/H+ exchange

• Published in: Drug development research 2024-06, Vol.85 (4), p.e22198-n/a
• Main Authors: Jin, Hai, Wen, Guorong, Zhu, Jiaxing, Liu, Jielong, Li, Jingguo, Yao, Shun, Zhao, Zhenglan, Dong, Zhiqi, Zhang, Xue, An, Jiaxing, Liu, Xuemei, Tuo, Biguang
• Format: Article
• Language: English
• Subjects: Animal models; Animal tissues; Animals; Cancer; Carbon tetrachloride; Carcinogenesis; Carcinogenesis - drug effects; Carcinogens; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; CXCL10 protein; Cytokines; Cytokines - metabolism; Diet, High-Fat - adverse effects; Diethylnitrosamine; Diethylnitrosamine - toxicity; Exchanging; Genes; Glycolysis; Glycolysis - drug effects; Hepatocellular carcinoma; High fat diet; Humans; Hydrogen; Inflammation; Liver; Liver cancer; Liver Neoplasms - chemically induced; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Male; Mice; Mice, Inbred C57BL; Monocyte chemoattractant protein 1; Na+/H+-exchanging ATPase; pantoprazole; Pantoprazole - pharmacology; prevention and therapy
• ISSN: 0272-4391; 1098-2299
• DOI: 10.1002/ddr.22198

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The prevention and therapy for this deadly disease remain a global medical challenge. In this study, we investigated the effect of pantoprazole (PPZ) on the carcinogenesis and growth of HCC. Both diethylnitrosamine (DEN) plus CCl4‐induced and DEN plus high fat diet (HFD)‐induced HCC models in mice were established. Cytokines and cell proliferation‐associated gene in the liver tissues of mice and HCC cells were analyzed. Cellular glycolysis and Na+/H+ exchange activity were measured. The preventive administration of pantoprazole (PPZ) at a clinically relevant low dose markedly suppressed HCC carcinogenesis in both DEN plus CCl4‐induced and HFD‐induced murine HCC models, whereas the therapeutic administration of PPZ at the dose suppressed the growth of HCC. In the liver tissues of PPZ‐treated mice, inflammatory cytokines, IL1, CXCL1, CXCL5, CXCL9, CXCL10, CCL2, CCL5, CCL6, CCL7, CCL20, and CCL22, were reduced. The administration of CXCL1, CXCL5, CCL2, or CCL20 all reversed PPZ‐suppressed DEN plus CCL4‐induced HCC carcinogenesis in mice. PPZ inhibited the expressions of CCNA2, CCNB2, CCNE2, CDC25C, CDCA5, CDK1, CDK2, TOP2A, TTK, AURKA, and BIRC5 in HCC cells. Further results showed that PPZ reduced the production of these inflammatory cytokines and the expression of these cell proliferation‐associated genes through the inhibition of glycolysis and Na+/H+ exchange. In conclusion, PPZ suppresses the carcinogenesis and growth of HCC, which is related to inhibiting the production of inflammatory cytokines and the expression of cell proliferation‐associated genes in the liver through the inhibition of glycolysis and Na+/H+ exchange.