Key Structure of Brij for Overcoming Multidrug Resistance in Cancer

Multidrug resistance (MDR) is a major barrier to the chemotherapy treatment of many cancers. However, some nonionic surfactants, for example, Brij, have been shown to restore the sensitivity of MDR cells to such drugs. The aim of this study was to explore the reversal effect of Brij on MDR tumor cells and elucidate its potential mechanism. Our data indicate that the structure of Brij surfactants plays an important role in overcoming MDR in cancer, that is, modified hydrophilic-lipophilic balance (MHLB, the ratio of the number (n) of hydrophilic repeating units of ethylene oxide (EO) to the number (m) of carbons in the hydrophobic tail (CH(2))). Cell viability of cells treated with paclitaxel (PTX) nanocrystals (NCs) formulated with Brij showed positive correlations with MHLB (R(2) = 0.8195); the higher the ratio of Brij to PTX in NCs, the higher cytotoxicity induced by the PTX NCs. Significant increases in intracellular accumulation of (3)H-PTX (P-gp substrate) were observed in an MDR cell line (H460/taxR cells) treated with Brij 78 (MHLB = 1.11) and Brij 97 (MHLB = 0.6). After treatments with Brij 78 and Brij 97, the levels of intracellular ATP were decreased and verapamil-induced ATPase activities of P-gp were inhibited in multidrug resistant cells. The responses of the cells to Brij 78 and Brij 97 in ATP depletion studies correlated with the cell viability induced by PTX/Brij NCs and intracellular accumulation of (3)H-PTX. Brij 78 and Brij 97 could not alter the levels of P-gp expression detected by Western blotting. These findings may provide some insight into the likelihood of further development of more potent P-gp inhibitors for the treatment of MDR in cancer.