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Novel steroid carbamates reverse multidrug-resistance in cancer therapy and show linkage among efficacy, loci of drug action and P-glycoprotein's cellular localization

Argov, Mirit; Bod, Tal; Batra, Satish LU and Margalit, Rimona (2010) In European Journal of Pharmaceutical Sciences 41(1). p.53-59
Abstract
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 mu M, each new candidate: (i) increased cytotoxicity of doxorubicin (15-fold)... (More)
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 mu M, each new candidate: (i) increased cytotoxicity of doxorubicin (15-fold) and (separately) of paclitaxel (40-fold), (ii) induced an increase in intracellular accumulation, 60% (4 h) for doxorubicin and 300% (18 h) 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. (C) 2010 Elsevier B.V. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
p-glycoprotein, Cell-membrane, Multidrug-resistance, Intracellular p-glycoprotein, Novel chemosensitizers, Cancer
in
European Journal of Pharmaceutical Sciences
volume
41
issue
1
pages
53 - 59
publisher
Elsevier
external identifiers
  • wos:000280875700007
  • scopus:77954763228
ISSN
1879-0720
DOI
10.1016/j.ejps.2010.05.012
language
English
LU publication?
yes
id
138f9f52-797c-43dc-9ecd-fa503e2babba (old id 1676779)
date added to LUP
2010-09-22 08:08:03
date last changed
2018-05-29 11:26:31
@article{138f9f52-797c-43dc-9ecd-fa503e2babba,
  abstract     = {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 mu M, each new candidate: (i) increased cytotoxicity of doxorubicin (15-fold) and (separately) of paclitaxel (40-fold), (ii) induced an increase in intracellular accumulation, 60% (4 h) for doxorubicin and 300% (18 h) 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. (C) 2010 Elsevier B.V. All rights reserved.},
  author       = {Argov, Mirit and Bod, Tal and Batra, Satish and Margalit, Rimona},
  issn         = {1879-0720},
  keyword      = {p-glycoprotein,Cell-membrane,Multidrug-resistance,Intracellular p-glycoprotein,Novel chemosensitizers,Cancer},
  language     = {eng},
  number       = {1},
  pages        = {53--59},
  publisher    = {Elsevier},
  series       = {European Journal of Pharmaceutical Sciences},
  title        = {Novel steroid carbamates reverse multidrug-resistance in cancer therapy and show linkage among efficacy, loci of drug action and P-glycoprotein's cellular localization},
  url          = {http://dx.doi.org/10.1016/j.ejps.2010.05.012},
  volume       = {41},
  year         = {2010},
}