Diterpenoids from Euphorbia royleana reverse P-glycoprotein-mediated multidrug resistance in cancer cells. (August 2020)

• Record Type: Journal Article
• Authors: Shaker, Sharpkate; Sang, Jun; Yan, Xue-Long; Fan, Run-Zhu; Tang, Gui-Hua; Xu, You-Kai; Yin, Sheng
• Is Part Of: Phytochemistry. Volume 176(2020)
• Publication Date: 2020-08
• Subjects: Euphorbiaceae -- Euphorbia royleana -- Diterpenoids -- Multidrug resistance (MDR) -- P-glycoprotein; Botanical chemistry -- Periodicals; Biochemistry -- Periodicals; Botany -- Periodicals; Chimie végétale -- Périodiques; 572.2
• DOI: 10.1016/j.phytochem.2020.112395
• Languages: English
• ISSNs: 0031-9422

Abstract

Abstract: Eight previously undescribed diterpenoids, euphoroyleans A−H, including two cembranes, three ingenanes, two ent -atisanes, and one ent -kaurane, along with 22 known analogues were isolated from the whole plants of Euphorbia royleana . The structures of euphoroyleans A−H, including the absolute configurations, were elucidated by extensive spectroscopic analyses, chemical transformation, and single crystal X-ray diffractions. All the isolates were screened for their chemoreversal abilities on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) cancer cell line HepG2/DOX, and eight compounds exhibited significant activities. Among them, ingol-3, 7, 12-triacetate-8-benzoate, the most active MDR modulator with no obvious cytotoxicity, could enhance the efficacy of anticancer drug DOX to ca . 105 folds at 10 μ M, being stronger than the positive drug verapamil. Mechanistic study revealed that ingol-3, 7, 12-triacetate-8-benzoate could inhibit the transport activity of P-gp rather than its expression, and the possible recognition mechanism between compounds and P-gp was predicted by molecular docking. Graphical abstract: Eight previously undescribed diterpenoids, along with 22 known analogues were isolated from Euphorbia royleana . Ingol-3, 7, 12-triacetate-8-benzoate was identified as a potent multidrug resistance (MDR) modulator with no obvious cytotoxicity. It could inhibit the transport activity of P-glycoprotein and enhance the efficacy of anticancer drug DOX to ca . 105 folds at 10 μM. Image 1 Highlights: Eight previously undescribed diterpenoids were isolated from Euphorbia royleana. Eight compounds exhibited significant chemoreversal activities. Ingol-3, 7, 12-triacetate-8-benzoate could enhance the efficacy of anticancer drug DOX to ca. 105 folds at 10 μM.