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오렌지 껍질로부터 분리된 프라보노이드의 화학요법 감작효과
최철익,변익건,차윤정,김선필,민영돈,유진철,송재경 조선대학교 2001 The Medical Journal of Chosun University Vol.26 No.2
Background and Objectives : The overexpression of P-glycoprotein (Pgp) or multidrug resistanceassociated protein (MRP) confers multidrug resistance (MDR) to cancer cells. MDR cells could be sensitized to anticancer drugs when treated concomitantly with a chemosensitizer. In this study, orange peel have been screened for the development of chemosensitizers reversing MDR. Materials and methods : Expression of Pgp in AML-2/WT and AML-2/D100 were determined using western blot analysis and RT-PCR. Candidates for chemosensitizers were isolated, purified from orange peel using sephadex LH-20 column chromatography and silica-gel column chromatography, whose structure was determined using ^1H-NMR, ^13C-NMR, ^1H-^1H-COSY, 13C-NMR, EI-Mass, IR. Chemosensitizing effect of NP-28 on AML-2/DX100 over expressing Pgp and MRP was determined by the MTT assay. Membrane toxicity was evaluated by the RBC hemolysis test. Antioxidant effects were examined by using a fluorescence probe (2’-7’-dichlorofluorescein diacetate). Results : A potent candidate, NP-28, has a flavonoid nucleus with some methoxy moiety. NP-28 is believed to have high therapeutic index, being non-transportable inhibitor and possibly, of inhibiting other efflux pumps such as MRP and antioxidant effects. NP-28 is also unlikely to be a substrate of Pgp. NP-28 did not increase Pgp levels. Conclusion : NP-28 has a Chemosensitizing effect to reverse Pgp-mediated MDR by increasing the intracellular accumulation of drugs. Furthermore, they do not increase expression of Pgp, which can allow a long term use without the concern about Pgp activation. NP-28 is anticipated as an ideal second-generation flavonoid chemosensitizer and/or possibly other therapeutic agents by further investigation.
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