Abstract
Thermal ablation in combination with transarterial chemoembolization (TACE) has been reported to exert a more powerful antitumor effect than thermal ablation alone in hepatocellular carcinoma patients. However, the underlying mechanisms remain unclear. The purpose of the present study was to evaluate whether sublethal hyperthermia encountered in the periablation zone during thermal ablation enhances the anticancer activity of doxorubicin in chronically hypoxic (encountered in the tumor area after TACE) liver cancer cells and to explore the underlying mechanisms. In the present study, HepG2 cells precultured under chronic hypoxic conditions (1% oxygen) were treated in a 42°C water bath for 15 or 30 min, followed by incubation with doxorubicin. Assays were then performed to determine intracellular uptake of doxorubicin, cell viability, apoptosis, cell cycle, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and total antioxidant capacity. The results confirmed that sublethal hyperthermia enhanced the intracellular uptake of doxorubicin into hypoxic HepG2 cells. Hyperthermia combined with doxorubicin led to a greater inhibition of cell viability and increased apoptosis in hypoxic HepG2 cells as compared with hyperthermia or doxorubicin alone. In addition, the combination induced apoptosis by increasing ROS and causing disruption of MMP. Pretreatment with the ROS scavenger N-acetyl cysteine significantly inhibited the apoptotic response, suggesting that cell death is ROS-dependent. These findings suggested that sublethal hyperthermia enhances the anticancer activity of doxorubicin in hypoxic HepG2 cells via a ROS-dependent mechanism.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide [1,2]
The results showed that sublethal hyperthermia significantly enhanced the intracellular uptake of doxorubicin in HepG2 cells precultured under chronically hypoxic conditions (36.17% +− 6.29% for 15 min and 40.33% +− 8.27% for 30 min vs. 21.47% +− 4.82%, P
We have previously reported that chronic hypoxia up-regulates the gene expression of NRF2/ABCB1 and PARP-1 in HepG2 cells
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide [1,2]. Thermal ablation, predominantly radiofrequency ablation (RFA) and microwave ablation (MWA), has shown excellent therapeutic efficacy in HCC and is a commonly used therapy following surgery and embolotherapy (transarterial chemoembolization/transarterial embolization, TACE/TAE) [3,4,5]. Several studies have shown that RFA can achieve complete necrosis in most lesions smaller than 3 cm in diameter [6,7]. For lesions larger than 3 cm in diameter, especially for those over 5 cm, complete necrosis cannot be obtained in a minority of patients, even if the procedure is repeated. Several studies have shown that TACE in combination with RFA increases the size of the ablation zone as compared with RFA treatment alone, and the efficacy has been demonstrated in the treatment of small and medium-sized HCC [10,11,12,13].
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