One molecule two goals: A selective P-glycoprotein modulator increases drug transport across gastro-intestinal barrier and recovers doxorubicin toxicity in multidrug resistant cancer cells.

Abstract

In the present study a series of tetrahydroisoquinoline derivatives were synthesized and evaluated for their activity towards three ABC transporters, P-gp, MRP1 and BCRP. The compounds proved to be selective against P-gp. One of them, 8b, displayed activity in the nanomolar range (EC50 = 94 nM). Thus, compound 8b was tested for its ability to restore the cytotoxic activity of a well-known anti-cancer agent and P-gp substrate, doxorubicin, as first proof of concept. Moreover, compound 8b was also tested in an in vitro model of competent gastro-intestinal (GI) barrier (Caco-2 cells) for its ability to inhibit P-gp, present on luminal side, and increase the apical-to-basolateral transport of several structurally uncorrelated drugs, belonging to different therapeutic areas but actively excreted by P-gp. Notably the transport of the drugs across the GI barrier was increased by a concentration of 8b devoid of toxicity and of perturbing effects on barrier function. An in vitro simulated digestion process was set up: interestingly the effect of 8b on the transport of digoxin was preserved also after the simulated digestion process. This result may suggest 8b as a safe and effective P-gp modulator that can increase the bioavailability of a wide spectrum of drugs administered per os, improving their transport across the GI barrier.

• Authors: Marialessandra Contino, Stefano Guglielmo, Chiara Riganti, Giulia Antonello, Maria Grazia Perrone, Roberta Giampietro, Barbara Rolando, Roberta Fruttero, Nicola A Colabufo
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 208 Pg. 112843 (Dec 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 33007664 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Isoquinolines
• Doxorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Caco-2 Cells
• Dogs
• Doxorubicin (chemical synthesis, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Isoquinolines (chemical synthesis, pharmacology)
• Madin Darby Canine Kidney Cells
• Proof of Concept Study