Probable Mechanisms of Doxorubicin Antitumor Activity Enhancement by Ginsenoside Rh2

Abstract

Ginsenoside Rh2 increases the efficacy of doxorubicin (DOX) treatment in murine models of solid and ascites Ehrlich’s adenocarcinoma. In a solid tumor model (treatment commencing 7 days after inoculation), DOX + Rh2 co-treatment was significantly more efficacious than DOX alone. If treatment was started 24 h after inoculation, the inhibition of tumor growth of a solid tumor for the DOX + Rh2 co-treatment group was complete. Furthermore, survival in the ascites model was dramatically higher for the DOX + Rh2 co-treatment group than for DOX alone. Mechanisms underlying the combined DOX and Rh2 effects were studied in primary Ehrlich’s adenocarcinoma-derived cells and healthy mice’s splenocytes. Despite the previously established Rh2 pro-oxidant activity, DOX + Rh2 co-treatment revealed no increase in ROS compared to DOX treatment alone. However, DOX + Rh2 treatment was more effective in suppressing Ehrlich adenocarcinoma cell adhesion than either treatment alone. We hypothesize that the benefits of DOX + Rh2 combination treatment are due to the suppression of tumor cell attachment/invasion that might be effective in preventing metastatic spread of tumor cells. Ginsenoside Rh2 was found to be a modest activator in a Neh2-luc reporter assay, suggesting that Rh2 can activate the Nrf2-driven antioxidant program. Rh2-induced direct activation of Nrf2 might provide additional benefits by minimizing DOX toxicity towards non-cancerous cells.

Anticancer therapeutic effect of ginsenosides through mediating reactive oxygen species

“…The upregulation of the Nrf2-driven antioxidative signaling pathway may also contribute to chemoresistance in cancer cells. Chian et al studied this mechanism and verified that the ginsenoside Rd could, indeed, work against cisplatin-resistant lung cancer by downregulating this signaling pathway (Chian et al, 2019), which is consistent with the mechanism derived by Popov et al in a study on the enhancement of the anticancer effect of DOX by RH2 (Popov et al, 2022). Moreover, both Rg1 and Rh2 may serve as chemosensitizers of doxorubicin, which suppresses the NF-κB signaling pathway to inhibit Dox-induced SASP (IL-8 and TNFα), thereby rescuing the viability of normal mammary epithelial cells and maintaining an inhibitory effect on cancer proliferation.…”

Heterologous expression of Bacillus subtilis SL-44 glycosyltransferase catalyzed synthesis of ginsenoside Rh2

“…In the literature [13], glycogen-based nanoparticles, which are pH and redox-sensitive and can carry ginsenoside Rh2, were used for the treatment of ulcerative colitis, and such nanoparticles can release ginsenoside Rh2 in the intestinal environment to exert therapeutic effects. In the literature [14], ginsenoside Rh2 was found to enhance the antitumor effects of doxorubicin, and ginsenoside Rh2 can enhance the antitumor effects of Doxorubicin through various mechanisms, including enhancement of the toxic effects of Doxorubicin on tumor cells, inhibition of tumor cell proliferation, and reduction of cell migration.…”