Lycorine Carbamate Derivatives for Reversing P-glycoprotein-Mediated Multidrug Resistance in Human Colon Adenocarcinoma Cells

• Published in: International journal of molecular sciences Vol. 24; no. 3; p. 2061
• Main Authors: Sancha, Shirley A R, Szemerédi, Nikoletta, Spengler, Gabriella, Ferreira, Maria-José U
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20.01.2023; MDPI
• Subjects: ABC transporters; Adenocarcinoma; Adenocarcinoma - drug therapy; Alzheimer's disease; Amaryllidaceae Alkaloids - pharmacology; Amaryllidaceae-type alkaloid; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Assaying; ATP Binding Cassette Transporter, Subfamily B; Breast cancer; Cancer therapies; carbamates; Carbamates (tradename); Carbamates - pharmacology; Carbon; Cell cycle; Cell Line, Tumor; Chemotherapy; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Cytotoxicity; Doxorubicin; Doxorubicin - pharmacology; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs; Efflux; Fibroblasts; Flow cytometry; Glycoproteins; Humans; Hydroxyl groups; lycorine; Multidrug resistance; Multidrug resistant organisms; Natural products; P-Glycoprotein; Pancratium maritimum; Pharmacokinetics; Proteins; Rhodamine; Verapamil; P-glycoprotein; Amaryllidaceae-type alkaloid; multidrug resistance; ABCB1; Pancratium maritimum; lycorine; carbamates
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24032061

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Aiming at generating a small library of anticancer compounds for overcoming MDR, lycorine ( ), a major Amaryllidaceae alkaloid isolated from , was derivatized. Thirty-one new compounds ( - ) were obtained by chemical transformation of the hydroxyl groups of lycorine into mono- and di-carbamates. Compounds - were evaluated as MDR reversers, through the rhodamine-123 accumulation assay by flow cytometry and chemosensitivity assays, in resistant human colon adenocarcinoma cancer cells (Colo 320), overexpressing P-glycoprotein (P-gp, ABCB1). Significant inhibition of P-gp efflux activity was observed for the di-carbamate derivatives, mainly those containing aromatic substituents, at non-cytotoxic concentrations. Compound , bearing a benzyl substituent, and compounds and with phenethyl moieties, were among the most active, exhibiting strong inhibition at 2 µM, being more active than verapamil at 10-fold higher concentration. In drug combination assays, most compounds were able to synergize doxorubicin. Moreover, some derivatives showed a selective antiproliferative effect toward resistant cells, having a collateral sensitivity effect. In the ATPase assay, selected compounds ( , , , , , and ) were shown to behave as inhibitors.