title: Key structure of brij for overcoming multidrug resistance in cancer.
abstract: 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.
authors: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599-7360, United States.
authors: Jingling
authors: J
authors: Tang
authors: Yongjun
authors: Y
authors: Wang
authors: Dun
authors: D
authors: Wang
authors: Yuhua
authors: Y
authors: Wang
authors: Zhenghong
authors: Z
authors: Xu
authors: Kelly
authors: K
authors: Racette
authors: Feng
authors: F
authors: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008175:Lung Neoplasms / Q000188:drug therapy; D053758:Nanoparticles; D017239:Paclitaxel / Q000494:pharmacology; D010938:Plant Oils / Q000494:pharmacology*; D000077423:Polidocanol; D011092:Polyethylene Glycols / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D010938:Plant Oils; D013501:Surface-Active Agents; D000077423:Polidocanol; D011092:Polyethylene Glycols; D000255:Adenosine Triphosphate; C033084:polyethylene glycol oleyl ether; C043444:octadecyl polyoxyethylene ether; D014700:Verapamil; D000251:Adenosine Triphosphatases; D017239:Paclitaxel