Glycycoumarin Sensitizes Liver Cancer Cells to ABT-737 by Targeting De Novo Lipogenesis and TOPK-Survivin Axis

Abstract

Glycycoumarin (GCM) is a representative of bioactive coumarin compounds isolated from licorice, an edible and medicinal plant widely used for treating various diseases including liver diseases. The purpose of the present study is to examine the possibility of GCM as a sensitizer to improve the efficacy of BH3 mimetic ABT-737 against liver cancer. Three liver cancer cell lines (HepG2, Huh-7 and SMMC-7721) were used to evaluate the in vitro combinatory effect of ABT-737/GCM. HepG2 xenograft model was employed to assess the in vivo efficacy of ABT-737/GCM combination. Results showed that GCM was able to significantly sensitize liver cancer cells to ABT-737 in both in vitro and in vivo models. The enhanced efficacy by the combination of ABT-737 and GCM was attributed to the inactivation of T-LAK cell-originated protein kinase (TOPK)-survivin axis and inhibition of de novo lipogenesis. Our findings have identified induction of TOPK-survivin axis as a novel mechanism rendering cancer cells resistant to ABT-737. In addition, ABT-737-induced platelet toxicity was attenuated by the combination. The findings of the present study implicate that bioactive coumarin compound GCM holds great potential to be used as a novel chemo-enhancer to improve the efficacy of BH3 mimetic-based therapy.

Targeted Inhibition of LPL/FABP4/CPT1 fatty acid metabolic axis can effectively prevent the progression of nonalcoholic steatohepatitis to liver cancer

“…From 8-week to 20-week of the STAM mice model, we used small-molecule inhibitors targeting LPL, FABP4 or CPT1 for intervention. By reviewing the literature, the concentrations of small-molecule inhibitors Orlistat, BMS309403 and Etomoxir were determined to be 100 mg/kg [42] , 15 mg/kg [43,44] and 15 mg/kg [45,46]. We observed that the intraperitoneal injection of small-molecule inhibitors could effectively reduce the number and size of liver tumors in STAM mice, indicating that NASH-related tumorigenesis and tumor growth were inhibited.…”

Biejiajian Pill Inhibits Carcinogenesis and Metastasis via the Akt/GSK-3β/Snail Signaling Pathway in Hepatocellular Carcinoma

“…Among them, Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of EMT via the AKT/GSK-3β/Snail signaling cascade (Yuan et al, 2019). Moreover, Wogonin (Tian et al, 2014), Ursolic acid (Yan et al, 2010), Zerumbone (Samad et al, 2018), 6-Gingerol (Weng et al, 2010), Coumarin (Zhang E. et al, 2018), Resveratrol (Gao et al, 2020), Rutin (Thomas et al, 2017), Oleanolic acid (Wang et al, 2018) were involved in regulating the proliferation, apoptosis, invasion, as well as metastasis of HCC. Oleanolic acid serves an anti-EMT effect in HCC by increasing iNOS dimerization, NO production, and NT of EMT-related proteins (Wang H. et al, 2019).…”

Protective effects of glycycoumarin on liver diseases

“…Our study with the sensitization effect of GCM on ABT‐737 demonstrated that the phosphorylation levels of AMPK and ACC (inhibitory phosphorylation) were enhanced by either GCM alone or the combination, indicating the key lipogenic enzyme activity of ACC was suppressed by GCM. Furthermore, we found that inhibition of ACC by its inhibitor orlistat led to significant increase of ABT‐737‐induced apoptosis of liver cancer cells in vitro and enhanced tumor growth inhibition in vivo (Zhang et al, ). These results indicated that the inhibition of ACC by GCM may contribute to its sensitization effect on ABT‐737.…”