Abstract
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.
Highlights
The resistance of tumor cells to many toxic antitumor drugs, which are used for chemotherapy of cancer and are dissimilar in chemical structure and mechanism of action, has long been a known phenomenon called multidrug resistance (MDR)
We found that the studied triterpene glycoside cucumarioside A2 -2 (CA2 -2) effectively blocks the activity of P-gp at
Blocking MDR in Ehrlich ascites carcinoma (EAC) cells and an increase in the fluorescence intensity of the Calcein probe accumulated in the cytoplasm amounted to about 50% as compared to control level to accumulated in the cytoplasm amounted to about 50% as compared to control level to standard MDR inhibitor, verapamil (Figure 1B)
Summary
The resistance of tumor cells to many toxic antitumor drugs, which are used for chemotherapy of cancer and are dissimilar in chemical structure and mechanism of action, has long been a known phenomenon called multidrug resistance (MDR). Cells that have MDR or acquire it during chemotherapy become resistant to the action of drugs and the destruction or inhibition of their proliferation requires the use of chemotherapeutic cytostatics such as cyclophosphamide, doxorubicin, vinblastine, cisplatin and fluorouracil in doses so large that they often cause unwanted toxic effects. The most common MDR mechanism is the activation of transmembrane transport proteins that remove various substances from the cell. P-gp acts as a pump which, using the energy of ATP, can pump a wide variety of substances from the cell including a variety of antitumor cytostatics and cytotoxins that freely penetrate through the cell membranes by diffusion. The use of new effective MDR blockers would help solve the problem arising from the use of chemotherapy
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