Effective MDR reversers through phytochemical study of Euphorbia boetica

Abstract

Introduction Macrocyclic diterpenes from Euphorbia species were found to be promising modulators of multidrug resistance (MDR), a complex phenomenon that hampers the effectiveness of cancer therapy. Objective To find new effective MDR reversers through the phytochemical study of E. boetica, including isolation and molecular derivatisation. Material and methods The phytochemical study of E. boetica was performed through chromatographic techniques. Preliminary analysis of crude chromatographic fractions from the methanol extract was carried out by 1H‐NMR in order to prioritise the study of those having macrocyclic diterpenes. Polyamide resin was used to remove chlorophylls. Molecular derivatisation of isolated compounds comprised hydrolysis, reduction and acylation reactions. The structural identification of compounds was performed through analysis of spectroscopic data, mainly one‐dimensional‐ and two‐dimensional‐NMR. The MDR reversing activity was assessed using a combination of transport and chemosensitivity assays, in mouse lymphoma (L5178Y‐MDR) and Colo320 cell models. Results The 1H‐NMR study of crude fractions and application of a straightforward method to remove chlorophylls, allowed the effortless isolation of two lathyrane‐type diterpenes in large amounts, including the new polyester, euphoboetirane B (1). Taking advantage of the chemical functions of 1, 13 new derivatives were prepared. Several compounds showed to be promising modulators of P‐glycoprotein (P‐gp), in resistant cancer cells. Most of the compounds tested revealed to interact synergistically with doxorubicin. Conclusion These results corroborate the importance of macrocyclic lathyrane diterpenes as effective lead compounds for the reversal of MDR.

In Vitro Modulation of P-Glycoprotein Activity by Euphorbia intisy Essential Oil on Acute Myeloid Leukemia Cell Line HL-60R

“…The combination of the essential oil (25 µg/mL) and doxorubicin at different concentrations in HL-60R cells also caused a significant potentiation in the induction of cell death (Table 6 and Figure S2). Our results agree with those reported by Neto et al [56] and Reies et al [57] that show that Euphorbia secondary metabolites were more efficient than verapamil in reverting MDR phenotypes. For this reason, we hypothesize that E. intisy EO can represent an effective and non-toxic P-gp inhibitor to reverse P-gp-mediated multidrug resistance and improve the potency of anticancer drugs.…”

Research Progress on Natural Diterpenoids in Reversing Multidrug Resistance

“…The activity of reversing MDR was evaluated using a combination of transport and chemosensitivity assays in L5178Y-MDR and Colo320 cell models. The results confirmed the importance of macrocyclic lathyrane diterpenes as effective lead compounds for reversing MDR ( Neto et al, 2019 ).…”

Phytochemicals: Potential Lead Molecules for MDR Reversal

“…Reis et al (2016) reported that jatrophane diterpenes including esulatin M, epoxywelwitschene, welwitschene, and euphowelwitschine A were more efficative in MDR cells than the positive control verapamil. In comparison to the known MDR modifier verapamil, euphoboetirane C, D, E, F, and G extracted from Euphorbia boetica showed multifold P-gp modulatory activity in L5178Y-MDR cells (Neto et al, 2019). Three types of latilagascenes (G, H and I), macrocyclic diterpene esters, were effective in L5178 cells expressing P-gp as transport inhibitors (Duarte et al, 2008).…”

“…Glaucine exerted synergistic interaction with DOX and even more in a three drug combination with DTN (Eid et al, 2013). Euphoboetirane C, D, F, G, H and I extracted from Euphorbia boetica showed strong synergistic interactions with DOX in L5178Y-MDR cells (Neto et al, 2019). Nobiletin and antofine showed synergistic interactions with PTX (Kim et al, 2012;Ma et al, 2015).…”