{"entity": "publication", "iuid": "c2adaa2de62b4ea698d03cd047e77187", "timestamp": "2026-08-26T22:46:28.878Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/c2adaa2de62b4ea698d03cd047e77187.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/c2adaa2de62b4ea698d03cd047e77187"}}, "title": "Epoxylathyrane Derivatives as MDR-Selective Compounds for Disabling Multidrug Resistance in Cancer.", "authors": [{"family": "Reis", "given": "Mariana Alves", "initials": "MA"}, {"family": "Matos", "given": "Ana M", "initials": "AM"}, {"family": "Duarte", "given": "No\u00e9lia", "initials": "N"}, {"family": "Ahmed", "given": "Omar Bauomy", "initials": "OB"}, {"family": "Ferreira", "given": "Ricardo J", "initials": "RJ"}, {"family": "Lage", "given": "Hermann", "initials": "H"}, {"family": "Ferreira", "given": "Maria-Jos\u00e9 U", "initials": "MU"}], "type": "journal article", "published": "2020-05-08", "journal": {"title": "Front. Pharmacol.", "issn": "1663-9812", "volume": "11", "pages": "599", "issn-l": "1663-9812"}, "abstract": "Multidrug resistance (MDR) has been regarded as one of the major hurdles for the successful outcome of cancer chemotherapy. The collateral sensitivity (CS) effect is one the most auspicious anti-MDR strategies. Epoxylathyrane derivatives 1-16 were obtained by derivatization of the macrocyclic diterpene epoxyboetirane A (17), a lathyrane-type macrocyclic diterpene isolated from Euphorbia boetica. Some of these compounds were found to strongly modulate P-glycoprotein (P-gp/ABCB1) efflux.\n\nThe main goal was to develop lathyrane-type macrocyclic diterpenes with improved MDR-modifying activity, by targeting more than one anti-MDR mechanism.\n\nIn this study, the potential CS effect of compounds 1-16 was evaluated against gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29) human cancer cells and their drug-resistant counterparts, respectively selected against mitoxantrone (EPG85-257RNOV; EPP85-181RNOV; HT-RNOV) or daunorubicin (EPG85-257RDB; EPP85-181RDB; HT-RDB). The most promising compounds (8, 15, and 16) were investigated as apoptosis inducers, using the assays annexin V/PI and active caspase-3.\n\nThe compounds were more effective against the resistant gastric cell lines, being the CS effect more significant in EPG85-257RDB cells. Taking together the IC50 values and the CS effect, compounds 8, 15, and 16 exhibited the best results. Epoxyboetirane P (8), with the strongest MDR-selective antiproliferative activity against gastric carcinoma EPG85-257RDB cells (IC50 of 0.72 \u00b5M), being 10-fold more active against this resistant subline than in sensitive gastric carcinoma cells. The CS effect elicited by compounds 15 and 16 appeared to be by inducing apoptosis via caspase-3 activation. Structure-activity relationships of the compounds were additionally obtained through regression models to clarify the structural determinants associated to the CS effect.\n\nThis study reinforces the importance of lathyrane-type diterpenes as lead molecules for the research of MDR-modifying agents.", "doi": "10.3389/fphar.2020.00599", "pmid": "32457612", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC7226783"}], "notes": [], "created": "2026-08-21T13:00:34.774Z", "modified": "2026-08-21T13:00:34.811Z"}