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Title: Interaction of forskolin with the P-glycoprotein multidrug transporter

Abstract

Forskolin and 1,9-dideoxyforskolin, an analogue that does not activate adenylyl cyclase, were tested for their ability to enhance the cytotoxic effects of adriamycin in human ovarian carcinoma cells, SKOV3, which are sensitive to adriamycin and express low levels of P-glycoprotein, and a variant cell line, SKVLB, which overexpresses the P-glycoprotein and has the multidrug reing ance (MDR) phenotype. Forskolin and 1,9-dideoxyforskolin both increased the cytotoxic effects of adriamycin in SKVLB cells, yet had no effect on SKOV3 cells. Two photoactive derivatives of forskolin have been synthesized, 7-O-((2-(3-(4-azido-3-({sup 125}I)iodophenyl)propionamido)ethyl)carbamyl)forskolin, {sup 125}I-6-AIPP-Fsk, and 6-O-((2-(3-(4-azido-3-({sup 125}I)iodophenyl)propionamido)ethyl)carbamyl)forskolin, {sup 125}I-6-AIPP-Fsk, which exhibit specificity for labeling the glucose transporter and aing lyl cyclase, respectively. Both photolabels identified a 140-kDa protein in membranes from SKVLB cells whose labeling was inhibited by forskolin and 1,9-dideoxyforskolin. The data are consistent with forskolin binding to the P-glycoprotein analogous to that of other chemosensitizing drugs that have been shown to partially reverse MDR. The ability of forskolin photolabels to specifically label the transporter, the adenylyl cyclase, and the P-glycoprotein suggests that these proteins may share a common biing g domain for forskolin analogues.

Authors:
;  [1]; ;  [2];  [3]
  1. (Food and Drug Administration, Bethesda, MD (United States))
  2. (Fox Chase Cancer Research Center, Philadelphia, PA (United States))
  3. (Univ. of Wisconsin, Madison (United States))
Publication Date:
OSTI Identifier:
5821973
Alternate Identifier(s):
OSTI ID: 5821973
Resource Type:
Journal Article
Journal Name:
Biochemistry; (United States)
Additional Journal Information:
Journal Volume: 30:34; Journal ID: ISSN 0006-2960
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; DRUGS; BIOLOGICAL EFFECTS; MEMBRANE PROTEINS; CROSS-LINKING; TERPENES; RADIORECEPTOR ASSAY; GLYCOPROTEINS; IODINE 125; BETA DECAY RADIOISOTOPES; CHEMICAL REACTIONS; DAYS LIVING RADIOISOTOPES; ELECTRON CAPTURE RADIOISOTOPES; INTERMEDIATE MASS NUCLEI; INTERNAL CONVERSION RADIOISOTOPES; IODINE ISOTOPES; ISOTOPE APPLICATIONS; ISOTOPES; NUCLEI; ODD-EVEN NUCLEI; ORGANIC COMPOUNDS; POLYMERIZATION; PROTEINS; RADIOISOTOPES; TRACER TECHNIQUES 550200* -- Biochemistry

Citation Formats

Ming s, D.I., Seamon, K.B., Speicher, L.A., Tew, K.D., and Ruoho, A.E. Interaction of forskolin with the P-glycoprotein multidrug transporter. United States: N. p., 1991. Web.
Ming s, D.I., Seamon, K.B., Speicher, L.A., Tew, K.D., & Ruoho, A.E. Interaction of forskolin with the P-glycoprotein multidrug transporter. United States.
Ming s, D.I., Seamon, K.B., Speicher, L.A., Tew, K.D., and Ruoho, A.E. Tue . "Interaction of forskolin with the P-glycoprotein multidrug transporter". United States.
@article{osti_5821973,
title = {Interaction of forskolin with the P-glycoprotein multidrug transporter},
author = {Ming s, D.I. and Seamon, K.B. and Speicher, L.A. and Tew, K.D. and Ruoho, A.E.},
abstractNote = {Forskolin and 1,9-dideoxyforskolin, an analogue that does not activate adenylyl cyclase, were tested for their ability to enhance the cytotoxic effects of adriamycin in human ovarian carcinoma cells, SKOV3, which are sensitive to adriamycin and express low levels of P-glycoprotein, and a variant cell line, SKVLB, which overexpresses the P-glycoprotein and has the multidrug reing ance (MDR) phenotype. Forskolin and 1,9-dideoxyforskolin both increased the cytotoxic effects of adriamycin in SKVLB cells, yet had no effect on SKOV3 cells. Two photoactive derivatives of forskolin have been synthesized, 7-O-((2-(3-(4-azido-3-({sup 125}I)iodophenyl)propionamido)ethyl)carbamyl)forskolin, {sup 125}I-6-AIPP-Fsk, and 6-O-((2-(3-(4-azido-3-({sup 125}I)iodophenyl)propionamido)ethyl)carbamyl)forskolin, {sup 125}I-6-AIPP-Fsk, which exhibit specificity for labeling the glucose transporter and aing lyl cyclase, respectively. Both photolabels identified a 140-kDa protein in membranes from SKVLB cells whose labeling was inhibited by forskolin and 1,9-dideoxyforskolin. The data are consistent with forskolin binding to the P-glycoprotein analogous to that of other chemosensitizing drugs that have been shown to partially reverse MDR. The ability of forskolin photolabels to specifically label the transporter, the adenylyl cyclase, and the P-glycoprotein suggests that these proteins may share a common biing g domain for forskolin analogues.},
doi = {},
journal = {Biochemistry; (United States)},
issn = {0006-2960},
number = ,
volume = 30:34,
place = {United States},
year = {1991},
month = {8}
}