Dihydrotanshinone Enhances The Anticancer Effects of Sorafenib on Hepatocellular Carcinoma by Inhibiting Akt Signaling Pathway Activation
10.16476/j.pibb.2023.0369
- VernacularTitle:二氢丹参酮通过抑制Akt信号通路激活来增强索拉非尼对肝细胞癌的抗癌作用
- Author:
Wei WANG
1
;
Sheng-Nan JIA
1
;
Sun-Fu FAN
2
;
Li-Shan XU
3
Author Information
1. Department of Anorectal Surgery, Zhejiang Hospital, Hangzhou 310030, China
2. Department of General Surgery, Zhejiang Hospital, Hangzhou 310030, China
3. Department of Hepatobiliary Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China
- Publication Type:Journal Article
- Keywords:
dihydrotanshinone;
sorafenib;
Akt;
hepatocellular carcinoma;
apoptosis
- From:
Progress in Biochemistry and Biophysics
2024;51(6):1445-1457
- CountryChina
- Language:English
-
Abstract:
ObjectiveSorafenib is a first-line only drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Resistance to sorafenib means that treatment outcomes are often unsatisfactory. Although the mechanism underlying sorafenib resistance remains unclear, resistance may occur through Akt signaling pathway activation in HCC. Dihydrotanshinone (DHT), a lipophilic component of traditional Chinese medicine Salvia miltiorrhiza Bunge, has multiple anti-tumor activities and inhibits Akt activation. The effect and mechanism of DHT combined with sorafenib on HCC have not been investigated. In this study, we investigate whether DHT potentiates the anti-cancer activities of sorafenib against HCC. MethodsIn this study, the effects of sorafenib and DHT on the viability, apoptosis and drug sensitivity of Huh7 and HepG2 cells were verified by Cell Counting Kit-8 (CCK-8) and flow cytometry. Akt, P-Akt, Caspase3, GSK-3β, P-GSK-3β, ribosomal protein S6 kinase (S6K), P-S6K, Cyclin D1, Bcl-xl, Bcl-2, and Bax expression levels were analyzed via Western blot. All data were statistically compared using one-way analysis of variance (ANOVA) and Dunnett test. Statistical analysis using SPSS 20.0 statistical software. ResultsDHT inhibit proliferation and promote apoptosis in HCC cells by reducing Akt activation. DHT inhibits the expression and activation of Akt downstream factors, including GSK-3β and S6K, which regulate the apoptotic response and are activated and upregulated by sorafenib treatment. Both sorafenib and DHT downregulate cyclin D1 expression and DHT upregulates Bax expression and downregulates Bcl-2 and Bcl-xl expression. However, sorafenib had little influence on Bcl-2 family protein expression. ConclusionDHT may enhance the proliferation inhibition and apoptosis induction of sorafenib in HCC cells by inhibiting the activation of Akt signaling pathway, thus enhancing the anticancer effect of sorafenib.
