Modulation of Doxorubicin Intracellular Accumulation and Anticancer Activity by Triterpene Glycoside Cucumarioside A2-2

The effect of treatment of Ehrlich ascites carcinoma (EAC) cells with multidrug resistance by holothurian triterpene glycoside, cucumarioside A2-2 (CA2-2) was evaluated. Calcein-AM efflux assay and doxorubicin (DOX) uptake and retention measurement in cancer cells, as well as determination of DOX cytotoxic and anticancer effects were applied. Treatment of EAC cells with CA2-2 (0.01–0.1 μM) blocked Calcein-AM and DOX efflux from cancer cells and increased the accumulation and cytotoxicity of DOX in EAC cells. Moreover, pre-treatment of mice with EAC by CA2-2 (10 μg/kg/5 days, intraperitoneal injection (i.p.)), then transplantation of tumor cells into fresh animals and subsequent treatment of these mice with DOX (2 mg/kg/3 days i.p.) significantly increased average life span (ALS) of mice bearing a tumor and therefore boosted the antitumor effect of doxorubicin in vivo.