Diterpenes from Euphorbia piscatoria: synergistic interaction of Lathyranes with doxorubicin on resistant cancer cells.
Four new diterpenes were isolated from the methanolic extract of Euphorbia piscatoria, two ent-abietanes (1, 2) and two lathyrane-type macrocyclic diterpenes (3, 4), along with three known diterpenes (5-7). Their structures were characterized by spectroscopic methods, mainly 1D and 2D NMR ((1)H, (13)C, DEPT, COSY, HMBC, HMQC, and NOESY) experiments. Compound 2, with an unusual structure, might be considered intermediate in the biosynthesis of ent-abietane α,β-unsaturated lactones, commonly found in Euphorbia species. Therefore, a possible biogenetic pathway is proposed. The MDR reversal potential of macrocyclic diterpenes 3-5 was evaluated through a drug combination assay, using the L5178Y mouse T lymphoma cell line transfected with the human MDR1 gene. Compounds 3-5 were able to enhance, synergistically, the antiproliferative activity of doxorubicin (combination indexes < 0.5). Moreover, compounds 1-6 were also assessed for their antiproliferative activity on human MDR cancer cell models, namely gastric, pancreatic, and colon. Weak antiproliferative activity was observed for compounds 1 (IC50 = 66.02 ± 7.10 µM) and 4 (IC50 = 39.51 ± 3.82 µM) on the MDR gastric cell line.
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
Mariana A
MA
Reis
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
Angela
A
Paterna
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
Andreia
A
Mónico
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Joseph
J
Molnar
Institute of Pathology, Charité Campus Mitte, Berlin, Germany.
Hermann
H
Lage
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
Maria-José U
MJ
Ferreira
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D028481:Euphorbia / Q000737:chemistry*; D008223:Lymphoma; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; C530347:lathyrane; D004317:Doxorubicin