Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 78, Issue 1, Pages 57-72Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1747-0285.2011.01089.x
Keywords
cancer; multidrug-resistance transporters; oxazepine; P-glycoprotein inhibitors; pharmacophore; virtual screening
Funding
- FCT [226/2003, 4040/07]
- FEDER
- POCI
- U.Porto
- Santander Totta
- FCT, the Portuguese Foundation for Science and Technology
Ask authors/readers for more resources
P-glycoprotein (P-gp) is one of the best characterized transporters responsible for the multidrug resistance phenotype exhibited by cancer cells. Therefore, there is widespread interest in elucidating whether existing drugs are candidate P-gp substrates or inhibitors. With this aim, a pharmacophore model was created based on known P-gp inhibitors and it was used to screen a database of existing drugs. The P-gp modulatory activity of the best hits was evaluated by several methods such as the rhodamine-123 accumulation assay using K562Dox cell line, and a P-gp ATPase activity assay. The ability of these compounds to enhance the cytotoxicity of doxorubicin was assessed with the sulphorhodamine-B assay. Of the 21 hit compounds selected in silico, 12 were found to significantly increase the intracellular accumulation of Rhodamine-123, a P-gp substrate. In addition, amoxapine and loxapine, two tetracyclic antidepressant drugs, were discovered to be potent non-competitive inhibitors of P-gp, causing a 3.5-fold decrease in the doxorubicin GI(50) in K562Dox cell line. The overall results provide important clues for the non-label use of known drugs as inhibitors of P-gp. Potent inhibitors with a dibenzoxazepine scaffold emerged from this study and they will be further investigated in order to develop new P-gp inhibitors.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available