taurochenodeoxycholic-acid and Ovarian-Neoplasms

Quercetin (3,3',4',5,7-pentahydroxyflavone, Qu) is a promising cancer chemo-preventive agent for various cancers because it inhibits disease progression and promotes apoptotic cell death. In our previous study, we demonstrated that Qu could evoke ER stress to enhance drug cytotoxicity in ovarian cancer (OC). However, Qu-induced ER stress in OC is still poorly understood. Here, we demonstrated that Qu evoked ER stress to involve in mitochondria apoptosis pathway via the p-STAT3/Bcl-2 axis in OC cell lines and in primary OC cells. Unexpectedly, inhibition of ER stress did not reverse Qu-induced cell death. Further functional studies revealed that Qu-induced ER stress could activate protective autophagy concomitantly by activating the p-STAT3/Bcl-2 axis in this process. Moreover, the autophagy scavenger 3-MA was shown to enhance Qu's anticancer effects in an ovarian cancer mice xenograft model. These findings revealed a novel role of ER stress as a "double edge sword" participating in Qu-induced apoptosis of OC and might provide a new angle to consider in clinical studies of biological modifiers that may circumvent drug resistance in patients by targeting protective autophagy pathways.

Topics: Adenine; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Cell Line, Tumor; Endoplasmic Reticulum Stress; Female; Humans; Mice; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Neoplasm Proteins; Ovarian Neoplasms; Quercetin; Random Allocation; RNA, Small Interfering; Signal Transduction; Specific Pathogen-Free Organisms; STAT3 Transcription Factor; Taurochenodeoxycholic Acid; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

Studies with multidrug resistance modifiers indicate that perturbations of the cell membrane structure may influence P-glycoprotein (P-gp)-mediated drug transport. We describe studies of plasma membrane order using electron-paramagnetic resonance (EPR) in resistant (CH(R)C5) and sensitive (AUXB1) chinese hamster ovary cells treated with R-verapamil and bile salts. Cell growth rates were determined in presence of doxorubicin mitomycin and cisplatin. The plasma membrane order in untreated resistant cells was higher than in the sensitive cells. Both the bile salt taurochenodeoxycholate (TCDC; 0.2-1.6 mM) and R-verapamil (1-3 microM) lowered the membrane order in the CH(R)C5 cells to that in the sensitive cells and reversed the resistance to doxorubicin and mitomycin. The bile salt tauroursodeoxycholate (TUDC; 0.2-3 mM) did not lower membrane order and did not sensitise CH(R)C5 cells. Neither R-verapamil, TCDC nor TUDC reduced the membrane order of the sensitive cells AUXB1 cells. These results support the view that changes in multidrug resistance in Chinese hamster ovary cells and P-gp function are associated with alterations in the fluidity of the plasma membrane.

Topics: Animals; Antineoplastic Agents; Cell Division; CHO Cells; Cisplatin; Cricetinae; Cricetulus; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Membrane Fluidity; Mitomycin; Ovarian Neoplasms; Taurochenodeoxycholic Acid; Tumor Cells, Cultured; Verapamil