| Project/Area Number |
10680567
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bioorganic chemistry
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| Research Institution | Osaka University |
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Principal Investigator |
KOBAYASHI Motomasa Professor, Graduate School of Pharmaceutical Sciences, 薬学研究科, 教授 (40116033)
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| Co-Investigator(Kenkyū-buntansha) |
AOKI Shunji Assistant Professor, Graduate School of Pharmaceutical Sciences, 薬学研究科, 助手 (60252699)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1999: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | multidrug resistant tumor cells / P-glycoprotein / multidrug resistance associated protein / araguspongines / cembrane diterpenes / agosterol A / KB-C2 cells / KB-CV60 cells / がん多剤耐性克服物質 / multidrug resistance protein / Spongia属海綿 / glutathione / araguspongine / Xestospongia属海綿 / 海洋生物 |
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| Research Abstract |
In the course of our study of bioactive substances from marine organisms, we focused on a search for reversing agents of multidrug resistance (MDR) in tumor cells. We used two kinds of MDR human epidermoid carcinoma cell lines, KB-C2 cells overexpressing P-glycoprotein (P-gp) and KB-CV60 cells overexpressing multidrug resistance associated protein (MRP) for the screening assay. We found that araguspongines conquered MDR in KB-C2 cells. Araguspongines were isolated from an Okinawan marine sponge of Xestospongia sp. and characterized as macrocyclic dimer of 2,9-disubstituted 1-oxaquinolizidine. Araguspongine D, which is a major component among araguspongines, completely conquered MDR in KB-C2 cells at 10 μg/ml. Araguspongines B and E, which were stereoisomers of araguspongine D, also completely reversed MDR in KB-C2 cells. 5,5'-N-Dimethyl derivative and 2,2'-diol synthesized from araguspongine E did not show reversing activity. We isolated cembrane-type diterpenes reversing MDR in KB-C2 cells from a soft coral of Sinularia sp. This cembranoid completely conquered MDR in KB-C2 cells at 10 μg/ml. This cembranoid is seemed to be an artifact compound, which was produced from known natural cembranolide by addition of n-BuOH. We synthesized a series of cembrane derivatives replaced the n-butyl ester with various alcohols and found that the reversing activity of those derivatives were related to the carbon number of alcohol. Agosterol A, a novel polyhydroxylated sterol acetate, was isolated from a marine sponge of Spongia sp. as a reversing agent of MDR. Agosterol A perfectly reversed resistance to colchitine in KB-C2 cells and resistance to vincristine in KB-CV60 cells at 3μM concentration. Agosterol A recovered the accumulation of vincristine in KB-C2 and KB-CV60 cells to the level equal to that of parental KB 3-1 cells at 3 μM concentration.
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