Ginsenoside Rg3 in combination with artesunate overcomes sorafenib resistance in hepatocellular carcinoma models

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the sixth most common cancer worldwide1. HCC is also the third leading cause of cancer deaths in the world2. Sorafenib, a multi-target tyrosine kinase inhibitor, can slow down the progression of HCC by inhibiting tyrosine kinases, which are essential for the proliferation of cancer cells. Unfortunately, the clinical effectiveness of sorafenib is often limited due to the development of drug resistance. Ginsenoside Rg3 (Rg3), a main bioactive triterpenoid saponin of red ginseng, is the active ingredient of the anti-cancer adjuvant drug “Shenyi Capsule”. Studies have indicated that Rg3 is able to overcome multi-drug resistance in cancer cells, and it can also synergize anti-HCC effects of sorafenib3. Artesunate (ART), an approved antimalarial drug, is a derivative of artemisinin, a sesquiterpene lactone found in the Chinese medicinal herb Artemisia annua. Pharmacological studies demonstrated that ART and sorafenib synergistically inhibit HCC tumor growth in mice4. It has been found that co-administration of Rg3 and ART can inhibit tumor growth in an S180 sarcoma mouse model5, but whether Rg3 and ART synergistically overcome sorafenib resistance in HCC is unknown. This study aimed to investigate the pharmacology effects and molecular mechanisms of Rg3-plus-ART in overcoming sorafenib resistance in HCC.

CCK8 assay results showed that Rg3-plus-ART exerted synergistic effects in reducing the viability of sorafenib-resistant HCC cells in time- and dose- dependent manners. Flow cytometric analyses indicated that Rg3-plus-ART induced apoptosis and S-phase cell cycle arrest in sorafenib-resistant HCC cells. Transwell assays demonstrated that Rg3-plus-ART could suppress the migratory and invasive abilities of sorafenib-resistant HCC cells.

In summary, Rg3-plus-ART synergistically overcomes sorafenib resistance in HCC cells. This study indicates that Rg3-plus-ART, discovered by drug repurposing, has the potential to be developed into an adjuvant drug for treating sorafenib-resistant HCC.