Abstract
Hepatocellular carcinoma (HCC) is difficult to treat, and is the second leading cause of cancer-related death worldwide. This study aimed to examine whether combination of wogonin and artesunate exhibits synergistic anti-HCC effect. Our data show that the combination treatment exhibits synergistic effect in reducing HCC cell viability by increasing apoptosis as indicated by the elevated cleavage of caspase 8, 3 and PARP. Interestingly, PCR array and the subsequent studies indicate that the combination treatment significantly increases the expression of DNA-damage-inducible, alpha (GADD45A), tumor necrosis factor (TNFα) and TNF receptor-associated factor 3 (TRAF3). Knockdown of GADD45A, TNFα or TRAF3 abolishes the combination treatment-enhanced apoptosis and the synergistic effect in reducing HCC cell viability. In the HCC-bearing xenograft mouse models, although the combination treatment increases the activity of NFκB in the tumor tissues, it exhibits a more potent anti-HCC effect than the mono-treatment, which may due to the enhanced apoptosis as indicated by the increased expression of GADD45A, TNFα, TRAF3 and apoptotic markers. Our study clearly demonstrates that the combination of artesunate and wogonin exhibits synergistic anti-HCC effect, and support the further development of this combination as alternative therapeutics for HCC management.
Highlights
Hepatocellular carcinoma (HCC) accounts for around 75–90% of all the primary liver cancer cases (Ringehan et al, 2017)
Wogonin enhances the therapeutic effects of sorafenib in the treatment of HCC by increasing apoptosis and inhibiting autophagy (Rong et al, 2017). Given both artesunate and wogonin have anti-HCC effects, we aimed to examine whether combination of artesunate and wogonin will have synergistic effect in HCC treatment and whether the combination treatment will have a more potent anti-HCC effect than sorafenib
The synergy of artesunate and wogonin was determined by combination index (CI) based on the median-effect equation, derived from the mass-action law principle
Summary
Hepatocellular carcinoma (HCC) accounts for around 75–90% of all the primary liver cancer cases (Ringehan et al, 2017). It is the fifth most prevalent cancer (Lim and Torresi, 2021) and the second leading cause of cancer-related death worldwide (Lim and Torresi, 2021). Sorafenib exhibits significant effect in prolonging the overall survival of the HCC patients. These patients usually acquire resistance to sorafenib (Villanueva and Llovet, 2012). HCC is one of the most difficult to cure cancers because of its high heterogeneity that attributes to the development of chemo-resistance, and poses great challenges to the management (Yang et al, 2019; Cabral et al, 2020)
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