Au-24 as a potential thioredoxin reductase inhibitor in hepatocellular carcinoma cells
Gaopan Dong1, Xiaohan Ye2, Shumei Wang3
1Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, China.
Abstract:
A novel TrxR inhibitor Au-24 and its inhibitory ability to hepatocellular carcinoma in vitro and in vivo is reported herein. Au-24 can suppress HepG2 cells from proliferating by lowering mitochondrial membrane potential (MMP) and increasing reactive oxygen species (ROS) levels, resulting in oxidative stress, which causes DNA damage, autophagy, cell cycle arrest, and apoptosis. This compound can also affect the normal function of apoptosis, MAPK, PI3K/AKT/mTOR, NF-κB, STAT3 signaling pathways. In vivo experiments revealed that Au-24 inhibited HepG2 tumor growth more effectively than AA1 (chloro(triethylphosphine)gold(I)) by decreasing Ki67 and CD31 protein expression and promoting tumor cell apoptosis and necrosis lesions. As a result, Au-24 was found to be a promising candidate as a TrxR inhibitor for the treatment of hepatocellular carcinoma (HCC) in both in vivo and in vitro experiments.
Insights
A novel thioredoxin reductase (TrxR) inhibitor, Au-24, effectively suppressed hepatocellular carcinoma (HCC) cell proliferation and tumor growth in vitro and in vivo. Au-24 shows promise for HCC treatment by inducing oxidative stress and apoptosis.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) remains a significant global health challenge.
- Thioredoxin reductase (TrxR) is a key enzyme implicated in cancer cell survival and proliferation.
- Targeting TrxR presents a potential therapeutic strategy for HCC.
Purpose of the Study:
- To investigate the inhibitory potential of a novel TrxR inhibitor, Au-24, against hepatocellular carcinoma (HCC).
- To evaluate the efficacy of Au-24 in both in vitro and in vivo HCC models.
Main Methods:
- In vitro studies utilized HepG2 cells to assess Au-24's effects on proliferation, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) levels, DNA damage, autophagy, cell cycle, and apoptosis.
- The impact of Au-24 on key signaling pathways including apoptosis, MAPK, PI3K/AKT/mTOR, NF-κB, and STAT3 was examined.
- In vivo experiments involved implanting HepG2 tumors and comparing the efficacy of Au-24 with AA1, assessing tumor growth, Ki67, CD31 expression, apoptosis, and necrosis.
Main Results:
- Au-24 suppressed HepG2 cell proliferation by reducing MMP and increasing ROS, leading to oxidative stress, DNA damage, autophagy, cell cycle arrest, and apoptosis.
- Au-24 modulated apoptosis, MAPK, PI3K/AKT/mTOR, NF-κB, and STAT3 signaling pathways.
- In vivo, Au-24 demonstrated superior inhibition of HepG2 tumor growth compared to AA1, evidenced by decreased Ki67 and CD31 expression and increased tumor cell apoptosis and necrosis.
Conclusions:
- Au-24 exhibits potent anti-cancer activity against hepatocellular carcinoma (HCC) through mechanisms involving oxidative stress induction and apoptosis.
- The compound effectively inhibits tumor growth in vivo, suggesting its therapeutic potential.
- Au-24 represents a promising TrxR inhibitor candidate for the treatment of HCC.
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