Role of ginsenoside Rb1 and its metabolite compound K in attenuating chemoresistance and tumour-initiating properties of ovarian cancer cells

Abstract

Resistance to therapy by traditional chemotherapy drugs commonly seen in ovarian cancer has been a major hurdle to developing successful treatment for the disease. Such chemoresistance is attributable to a subpopulation of cells known as cancer stem/tumour-initiating cells (jointly CSCs) within tumours that display characteristics of self-renewal, differentiation abilities, and serve as the primary drivers of tumourigenesis. CSCs are highly associated with therapeutic failures such as recurrent tumours and metastases. The use of adjuvants to sensitise cells to the drugs is an important field of current research, and ginsenosides are a class of candidate molecules. Of the several types of ginsenosides, Rb1 is one of the most prevalent and active ingredients of ginseng; hence the effects of Rb1 and its metabolite compound K (CK) on CSCs were investigated. Treatment with Rb1 and CK was found to inhibit the ability of ovarian cancer cells to form spheroids when cultured as CSCs, and reduce their expression of stem cell markers, Oct-4 and Nanog, and genes involved in drug resistance, ABCG2 and P-glycoprotein (P-gp), in a dose- and time-dependent manner. More importantly, treatment of Rb1 or CK could potentiate the anti-tumour effect of the front-line chemotherapeutic drugs paclitaxel or cisplatin. The combined treatment of Rb1 or CK with paclitaxel or cisplatin significantly reduced tumour-sphere forming ability as well as the cell viability of ovarian CSCs. These effects were associated with decreases in the expression of epithelial-to-mesenchymal transition transcriptional regulators Snail and Slug, concomitant with a decrease of N-cadherin and an increase of E-cadherin known to regulate stem-like properties. There was also an increase in cleaved caspase-3 levels, suggesting that the observed growth inhibition was due to apoptosis. Together, these findings suggest that Rb1 or CK in combination with a chemotherapeutic regimen may be a promising approach in cancer therapy.