1999 Fiscal Year Final Research Report Summary
Search for Reversing Agents of Multidrug-Resistance in Tumor Cells from Marine Organisms
| Project/Area Number |
10680567
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Bioorganic chemistry
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
KOBAYASHI Motomasa Professor, Graduate School of Pharmaceutical Sciences, 薬学研究科, 教授 (40116033)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
AOKI Shunji Assistant Professor, Graduate School of Pharmaceutical Sciences, 薬学研究科, 助手 (60252699)
|
|---|
| Project Period (FY) |
1998 – 1999
|
| Keywords | multidrug resistant tumor cells / P-glycoprotein / multidrug resistance associated protein / araguspongines / cembrane diterpenes / agosterol A / KB-C2 cells / KB-CV60 cells |
|---|
| 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.
|
-
-
-
-
-
-
-
-
[Publications] S. Aoki, Y. Yoshioka, Y. Miyamoto, K. Higuchi, A. Setiawan, N. Murakami, Z. S. Chen, T. Sumizawa, S. Akiyama, and M. Kobayashi: "Agostereol A, a novel polyhydroxylated sterol acetate reversing multidrug resistance from a marine sponge of Spongia sp."Tetrahedron Lett.. 39. 6303-6306 (1998)
Description
「研究成果報告書概要(欧文)」より
-
-
