Reversal of P-glycoprotein-mediated multidrug resistance to chemotherapeutic agents by natural products
Abstract
The development of resistance to multiple structurally unrelated drugs is considered to be one of the major obstacles in the successful treatment of various types of cancer. This multidrug resistance (MDR) phenomenon is largely attributed to the overexpression of a 170 kD glycoprotein (P-glycoprotein) which serves as a transmembrane efflux pump in extruding a number of natural anticancer drugs such as adriamycin and paclitaxel. To discover compounds from natural sources that reverse P-glycoprotein resistance to adriamycin in vitro, the bicinchoninic acid (BCA) assay developed in our lab was validated. The assay was then used for bioactivity-directed fractionation of Stephania japonica and two known compounds were isolated, Trilobine and Isotrilobine. Isotrilobine showed activity in the BCA assay comparable to that of verapamil, the standard multidrug-reversing agent. In addition, six taxoids were isolated from $Taxus\times media$ "Dark Green Spreader" and evaluated for their cytotoxicity as well as MDR-reversing activity. Five known compounds, Taxuspine F, Taxinine A, 2-Deacetoxydecinnamoyltaxinine J, I-Acetyl-10-deacetylbaccatin III, and 13-Deacetyldecinnamoyltaxinine J and a novel compound, 7-Deacetyldecinnamoyltaxuspine B, were isolated. The conformation of 7-Deacetyldecinnamoyltaxuspine B was determined by evaluation of NOESY NMR data and comparison of the data to three-dimensional structures. None of these taxoids were cytotoxic or demonstrated MDR-reversing activity. Other taxoids previously isolated or synthesized by our research group were tested for MDR-reversing activity. Experimental results indicated that resistant cells exhibited resistance to these compounds as well as to adriamycin. These taxoids, therefore, appear to be good substrates for the Pgp efflux pump and are inactive in MDR-reversing activity.
Degree
Ph.D.
Advisors
Chang, Purdue University.
Subject Area
Pharmacology|Analytical chemistry|Biochemistry|Oncology
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