Diterpenes from Euphorbia piscatoria: Synergistic Interaction of Lathyranes with Doxorubicin on Resistant Cancer Cells

Abstract

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 (¹H, ¹³C, 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.

Key words

Euphorbia piscatoria - Euphorbiaceae - lathyrane macrocyclic diterpenes - abietane lactones - MDR-reversal

• References

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