• Journal of Integrative Natural Science
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• v.5 no.2
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• pp.72-78
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• 2012

Multidrug resistance is a major obstacle in cancer chemotherapy. Cancer cells efflux chemotherapeutic drug out of cell by means of transporter and reduce the active concentration of it inside cell. Such transporters are member of the ATP binding cassettes (ABC) protein. It includes P-gp, multiple resistant protein (MRP), and breast cancer resistant protein (BCRP). These proteins are widely distributed in the human cells such as kidney, lung, endothelial cells of blood brain barrier etc. However, there are number of drugs developed for it, but most of them are getting transported by it. So, still there is necessity of a good modulator, which could effectively combat the transport of chemotherapeutic agents. Natural products origin modulators were found to be effective against transporter such as flavonoids, which belongs to third generation modulators. They have advantage over synthetic inhibitor in the sense that they have simple structure and abundant in nature. This review focuses on the P-gp structure its architecture, efflux mechanism, herbal inhibitors and their mechanism of action.

• Journal of Integrative Natural Science
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• v.4 no.1
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• pp.23-30
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• 2011

Multidrug resistance (MDR) is one of the main obstacles in the chemotherapy of cancer. MDR is associated with the over expression of P-glycoprotein (P-gp), resulting in increased efflux of chemotherapy from cancer cells. Inhibiting P-gp as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing. First-generation agents were limited by unacceptable toxicity, whereas second-generation agents had better tolerability but were confounded by unpredictable pharmacokinetic interactions and interactions with other transporter proteins. Third-generation inhibitors have high potency and specificity for P-gp. Furthermore, pharmacokinetic studies to date have shown no appreciable impact on drug metabolism and no clinically significant drug interactions with common chemotherapy agents. Third-generation P-gp inhibitors have shown promise in clinical trials. The continued development of these agents may establish the true therapeutic potential of P-gp-mediated MDR reversal.

• The Korean Journal of Nuclear Medicine
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• v.37 no.6
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• pp.382-392
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• 2003

Purpose: Uptakes of Tc-99m MIBI (MIBI) and Tc-99m tetrofosmin (tetrofosmin) in human non-small cell lung cancer A549, multidrug-resistance associated protein (MRP) expressing cell, were investigated in vitro and in vivo. Materials and Methods: Western blot analysis and immunohistochemistry were used for detection of MRP in A549 cells with anti-MRPr1 antibody. Cellular uptakes of two tracers were evaluated at $100{\mu}M$ of verapamil (Vrp), $50{\mu}M$ of cyclosporin A (CsA) and $25{\mu}M$ of butoxysulfoximide (BSO) after incubation with MIBI and tetrofosmin for 30 and 50 min at $37^{\circ}C$, using single cell suspensions at $1{\times}10^6cells/ml$. Radioactivities in supernatants and pellets were measured with gamma well counter. A549 cells were inoculated in each flanks of 24 nude mice. Group 1 (Gr1) and Gr3 mice were treated with only MIBI or tetrofosmin, and Gr2 and Gr4 mice were treated with 70mg/kg of CsA i.p. for 1 hour before injection of 370KBq of MIBI or tetrofosmin. Mice were sacrificed at 10, 60 and 240 min. Radioactivities of organs and tumors were expressed as percentage injected dose per gram of tissue (%ID/gm). Results: Western blot analysis of the A549 cells detected expression of MRPr1 (190 kDa) and immunohistochemical staining of tumor tissue for MRPr1 revealed brownish staining in cell membrane but not P-gp. Upon incubating A549 cells for 60 min with MIBI and tetrofosmin, cellular uptake of MIBI was higher than that of tetrofosmin. Coincubation with modulators resulted in an increase in cellular uptakes of MIBI and tetrofosmin. Percentage increase of MIBI was higher than that of tetrofosmin with Vrp by 623% and 427%, CsA by 753% and 629% and BSO by 219% and 140%, respectively. There was no significant difference in tumoral uptakes of MIBI and tetrofosmin between Gr1 and Gr3. Percentage increases in MIBI (114% at 10 min, 257% at 60 min, 396% at 240 min) and tetrofosmin uptake (110% at 10 min, 205% at 60 min, 410% at 240 min) were progressively higher by the time up to 240 min with CsA. Conclusion: These results indicate that MIBI and tetrofosmin are suitable tracers for imaging MRP-mediated drug resistance in A549 tumors. MIBI may be a better tracer than tetrofosmin for evaluating MRP reversal effect of modulators.