Bivalves naturally exposed to toxic algae have mechanisms to prevent from harmful effects of diarrhetic shellfish poisoning (DSP) toxins. However, quite few studies have examined the mechanisms associated, and the information currently available is still insufficient. Multixenobiotic resistance (MXR) is ubiquitous in aquatic invertebrates and plays an important role in defense against xenobiotics. Here, to explore the roles of P-glycoprotein (P-gp) in the DSP toxins resistance in shellfish, complete cDNA of P-gp gene in the mussel Perna viridis was cloned and analyzed. The accumulation of okadaic acid (OA), a main component of DSP toxins, MXR activity and expression of P-gp in gills of P. viridis were detected after exposure to Prorocentrum lima, a dinoflagellate producing DSP toxins in the presence or absence of P-gp inhibitors PGP-4008, verapamil (VER) and cyclosporin A (CsA). The mussel P. viridis P-gp closely matches MDR/P-gp/ABCB protein from various organisms, having a typical sequence organization as full transporters from the ABCB family. After exposure to P. lima, OA accumulation, MXR activity and P-gp expression significantly increased in gills of P. viridis. The addition of P-gp-specific inhibitors PGP-4008 and VER decreased MXR activity induced by P. lima, but had no effect on the OA accumulation in gills of P. viridis. However, CsA, a broad-spectrum inhibitor of ABC transporter not only decreased MXR activity, but also increased OA accumulation in gills of P. viridis. Together with the ubiquitous presence of other ABC transporters such as MRP/ABCC in bivalves and potential compensatory mechanism in P-gp and MRP-mediated resistance, we speculated that besides P-gp, other ABC transporters, especially MRP might be involved in the resistance mechanisms to DSP toxins.

2011-12-01·Toxicology and Applied Pharmacology3区 · 医学

Contribution of aquaporin 9 and multidrug resistance-associated protein 2 to differential sensitivity to arsenite between primary cultured chorion and amnion cells prepared from human fetal membranes

3区 · 医学

Article

作者: Yuta Yoshino ; Bo Yuan ; Toshihiko Hirano ; Sachiko Tanaka ; Hiroo Toyoda ; Deanna L. Kroetz ; Toshikazu Kaise ; Makoto Takeichi

Arsenic trioxide (arsenite, As(III)) has shown a remarkable clinical efficacy, whereas its side effects are still a serious concern. Therefore, it is critical to understand the effects of As(III) on human-derived normal cells for revealing the mechanisms underlying these side effects. We examined the effects of As(III) on primary cultured chorion (C) and amnion (A) cells prepared from human fetal membranes. A significant dose-dependent As(III)-mediated cytotoxicity was observed in the C-cells accompanied with an increase of lactate dehydrogenase (LDH) release. Higher concentrations of As(III) were required for the A-cells to show cytotoxicity and LDH release, suggesting that the C-cells were more sensitive to As(III) than the A-cells. The expression levels of aquaporin 9 (AQP9) were approximately 2 times higher in the C-cells than those in the A-cells. Both intracellular arsenic accumulation and its cytotoxicity in the C-cells were significantly abrogated by sorbitol, a competitive AQP9 inhibitor, in a dose-dependent manner. The protein expression levels of multidrug resistance-associated protein (MRP) 2 were downregulated by As(III) in the C-cells, but not in the A-cells. No significant differences in the expression levels of MRP1 were observed between C- and A-cells. The protein expression of P-glycoprotein (P-gp) was hardly detected in both cells, although a detectable amount of its mRNA was observed. Cyclosporine A, a broad-spectrum inhibitor for ABC transporters, and MK571, a MRP inhibitor, but not PGP-4008, a P-gp specific inhibitor, potently sensitized both cells to As(III)-mediated cytotoxicity. These results suggest that AQP9 and MRP2 are involved in controlling arsenic accumulation in these normal cells, which then contribute to differential sensitivity to As(III) cytotoxicity between these cells.

2009-04-01·Anti-Cancer Drugs4区 · 医学

Inhibition of P-glycoprotein-mediated docetaxel efflux sensitizes ovarian cancer cells to concomitant docetaxel and SN-38 exposure

4区 · 医学

Article

作者: Ylikomi, Timo ; Grenman, Seija ; Miettinen, Susanna

The first-line treatment of ovarian cancer is based on cytoreductive surgery and the use of anticancer drugs. The main disadvantage in the usage of anticancer drugs is the wide capacity of cancer cells to acquire a resistance to chemotherapeutic agents and therefore new treatment strategies have to be developed and tested. In this study, the responses of seven ovarian carcinoma cell lines to docetaxel and a camptothecin derivative, SN-38, were evaluated. We further studied the expression of P-glycoprotein (P-gp), the best described mechanism of drug resistance, in these cells and the effect of treatment with a specific P-gp inhibitor (PGP-4008). Simultaneous treatment with docetaxel and SN-38 (docetaxel+SN-38) had an antagonistic growth effect that was not dependent on the administration schedule. Both drugs alone or in combination induced G2M cell cycle arrest. Docetaxel was a more potent inducer of apoptosis than SN-38, but simultaneous treatment with docetaxel+SN-38 decreased the proportion of apoptotic cells to the same level observed after exposure to SN-38 alone. SN-38 increased P-gp expression in all cell lines. PGP-4008 enhanced docetaxel-mediated growth inhibition and apoptosis, but it did not have an effect when used simultaneously with SN-38. When cells were treated with docetaxel, SN-38, and PGP-4008 simultaneously, the growth was inhibited more efficiently and the proportion of apoptotic cells was higher than that without PGP-4008. Thus, treatment of ovarian cancer cells with docetaxel+SN-38 may have antagonistic effects. The simultaneous administration of a P-gp inhibitor may prevent docetaxel efflux, thereby sensitizing cells to docetaxel and other chemotherapeutic agents.

100 项与 PGP-4008 相关的药物交易

登录后查看更多信息