P-glycoprotein (Pgp) is a major
ABC transporter responsible for multidrug-resistance (MDR) in
cancer chemotherapy. Pre-clinical MDR modulation studies identified promising chemosensitizers, but none are in the clinic yet. Two novel
progesterone-derived
carbamates (11-
carbamic acid N,N-dibenzyl
progesterone ester and 11-
carbamic acid N,N-dibutyl
progesterone ester) were examined as potential chemosensitizers in the Pgp-expressing human
colon cancer line HCT-15, applying the classical MDR-drugs
paclitaxel and
doxorubicin. The major findings were: (1) Pgp was expressed in the HCT-15 cells in both the cell and the nuclear membranes, (2) at the low dose range of 1-5 microM, each new candidate: (i) increased cytotoxicity of
doxorubicin (15-fold) and (separately) of
paclitaxel (40-fold), (ii) induced an increase in intracellular accumulation, 60% (4h) for
doxorubicin and 300% (18h) for
paclitaxel, (iii) reduced
drug efflux from the cell, 2-fold and 4-fold for
doxorubicin and for
paclitaxel, respectively. Based on detailed kinetic analysis, using
liposomes to model
paclitaxel diffusion through cell membranes, efflux slowdown can be attributed to reduction in the rate constant of
drug diffusion through Pgp, and not to Pgp blockage. Chemosensitization was consistently-better for
paclitaxel (cytosol-operating) than for
doxorubicin (nuclear-operating) implying linkage between
P-glycoprotein localization and loci of
drug action. Mapping intracellular locations of MDR-pumps may assist therapeutic strategies.