4.Focusing on the treatment of chronic hepatitis B.
Chinese Journal of Hepatology 2009;17(10):721-721
8.Oncogenic β-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis.
Fangming LIU ; Yuting WU ; Baohui ZHANG ; Shuhui YANG ; Kezhuo SHANG ; Jie LI ; Pengju ZHANG ; Weiwei DENG ; Linlin CHEN ; Liang ZHENG ; Xiaochen GAI ; Hongbing ZHANG
Chinese Medical Journal 2024;137(2):181-189
BACKGROUND:
Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1 ), the most frequently altered proto-oncogene in hepatic neoplasms.
METHODS:
Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( β-catenin Δ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-catenin Δ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro . Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV ); β-catenin lox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer.
RESULTS:
MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV ; β-catenin lox(ex3)/+ mice, which stimulated concurrent Ctnnb1- activated mutation and HBV infection in liver cancer.
CONCLUSION
MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.
Mice
;
Animals
;
Humans
;
Methotrexate/therapeutic use*
;
Mice, Nude
;
beta Catenin/metabolism*
;
Fibroblasts/metabolism*
;
Liver Neoplasms/metabolism*
;
Hepatitis B virus
;
Nucleotides
9.Effect of antiviral therapy on the prognosis of patients with chronic hepatitis B-related cirrhosis.
Guang-jun SONG ; Bo FENG ; Hui-ying RAO ; Jian WANG ; Lai WEI
Chinese Journal of Hepatology 2013;21(6):438-441
OBJECTIVETo conduct a meta-analysis to study the effect of antiviral therapy on the prognosis of patients with chronic hepatitis B (CHB)-related cirrhosis.
METHODSPubMed, EMBASE, the Cochrane Central Register of Controlled Trials, Chinese Biomedical Database, Chinese Journals Full-text Database, and Wan Fang Digital Journal Full-text Database were searched for studies on nucleoside analogues antiviral treatment outcome of patients with CHB-related cirrhosis (vs. controls without antiviral therapy) published between January 1998 and March 2012. Data extraction and quality assessment was performed by two independent investigators. Heterogeneity was assessed by the I2 index. In the case of homogeneity the random-effects model was applied, and in the case of heterogeneity the fixed-effects model was applied. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.
RESULTSSeven studies were included in the meta-analysis: one high-quality randomized-controlled trial (RCT) study, four prospective cohort studies, and two case-control studies. Compared to the control group, the group treated with antiviral therapy showed a significantly lower incidence of hepatocellular carcinoma (11.2%, 76/680 vs. 6.7%, 75/1116; OR = 0.56, 95% CI: 0.40 to 0.79, P = 0.001) and lower mortality (23.6%, 78/331 vs. 10.8%, 43/398; OR = 0.36, 95% CI: 0.23 to 0.55, P = 0.000).
CONCLUSIONAntiviral therapy with nucleoside analogues significantly reduces the incidence of hepatocellular carcinoma and mortality in patients with CHB-related cirrhosis.
Antiviral Agents ; therapeutic use ; Hepatitis B, Chronic ; complications ; diagnosis ; drug therapy ; Humans ; Liver Cirrhosis ; diagnosis ; drug therapy ; etiology ; Nucleotides ; therapeutic use ; Prognosis
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