Inhibition of P-glycoprotein-induced multidrug resistance by a clerodane-type diterpenoid from Sindora sumatrana.
The aim of the present study was to investigate the effects of di- and sesquiterpenoids isolated from the pods of Sindora sumatrana Miq. (Leguminosae) on P-glycoprotein (P-gp) function in an adriamycin-resistant human breast cancer cell line, MCF-7/ADR. Over-expression of P-gp is known to be one of the mechanisms involved in multidrug resistance (MDR), which is a major obstacle in clinical cancer treatment. Among six di- and sesquiterpenoids extracted from S. sumatrana, (+)-7beta-acetoxy-15,16-epoxycleroda-3,13(16),14-trien-18-oic acid (1) showed a strong P-gp inhibitory effect, as great as that of verapamil, a representative P-gp inhibitor. Compound 1 enhanced daunomycin accumulation more than fourfold and significantly decreased daunomycin efflux compared with control, resulting in a decrease in the IC(50) value for daunomycin. These results suggest that compound 1 inhibits the functioning of P-gp and, therefore, can be developed as an MDR-reversing agent.
Jung
Ho Jin
HJ
Division of Life and Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Korea.
Chung
Soo Yeon
SY
Nam
Joo-Won
JW
Chae
Song Wha
SW
Lee
Yoo-Jin
YJ
Seo
Eun-Kyoung
EK
Lee
Hwa Jeong
HJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D045785:Diterpenes, Clerodane / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D007887:Fabaceae / Q000737:chemistry*; D005260:Female; D006801:Humans; D015394:Molecular Structure
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004224:Diterpenes; D045785:Diterpenes, Clerodane