5-Oxo-hexahydroquinoline derivatives as modulators of P-gp, MRP1 and BCRP transporters to overcome multidrug resistance in cancer cells.

Abstract

Multidrug resistance (MDR) in cancer cells is often associated with overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2). Modulators of these transporters might be helpful in overcoming MDR. Moreover, exploiting collateral sensitivity (CS) could be another approach for efficient treatment of cancer. Twelve novel 5-oxo-hexahydroquinoline derivatives bearing different aromatic substitutions at C4, while having 2-pyridyl alkyl carboxylate substituents at the C3 were synthesized and evaluated for MDR reversal activity by flow cytometric determination of rhodamine 123, calcein and mitoxantrone accumulations in P-gp, MRP1 and BCRP-overexpressing cell lines, respectively. Furthermore, to confirm the P-gp inhibitory activity, the effect of compounds on the reduction of doxorubicin's IC50 of drug-resistant human uterine sarcoma cell line, MES-SA/DX5, was evaluated. Compounds D6, D5 and D3 (bearing 3-chlorophenyl, 2,3-dichlorophenyl and 4-chlorophenyl substituents at C4 position of 5-oxo-hexahydroquinoline core) were the most potent P-gp, MRP1 and BCRP inhibitors, respectively, causing significant MDR reversal at concentrations of 1-10 μM. Additionally, D4 (containing 3-flourophenyl) was the most effective MRP1-dependent CS inducing agent. Overall, chlorine containing compounds D6, C4 and D3 were capable of significant inhibition of all 3 important efflux pumps in cancer cells. Moreover, D6 also induced CS triggered by reducing glutathione efflux. In conclusion, some of the 5-oxo-hexahydroquinoline derivatives are effective efflux pump inhibitors capable of simultaneously blocking 3 important ABC transporters involved in MDR, and represent promising agents to overcome MDR in cancer cells.

• Authors: Sara Ranjbar, Ruttiros Khonkarn, Alexis Moreno, Hélène Baubichon-Cortay, Ramin Miri, Mehdi Khoshneviszadeh, Luciano Saso, Najmeh Edraki, Pierre Falson, Omidreza Firuzi
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 362 Pg. 136-149 (01 01 2019) ISSN: 1096-0333 [Electronic] United States
• PMID: 30391378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• 5-oxo-hexahydroquinoline
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Antibiotics, Antineoplastic
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Quinolines
• Doxorubicin
• Glutathione
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (physiology)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (physiology)
• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Cell Line
• Cricetinae
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Glutathione (metabolism)
• Humans
• Multidrug Resistance-Associated Proteins (physiology)
• Neoplasm Proteins (physiology)
• Neoplasms (drug therapy, metabolism)
• Quinolines (pharmacology)