Diterpenoids from Euphorbia royleana reverse P-glycoprotein-mediated multidrug resistance in cancer cells

Shaker, Sharpkate; Sang, Jun; Yan, Xue-Long; Fan, Run-Zhu; Xu, You-Kai; Yin, Sheng

doi:10.1016/j.phytochem.2020.112395

Cited by 29 publications

(35 citation statements)

References 29 publications

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“…Then, the Rho‐123 accumulation assay was conducted to examine its influence of 5 on the P‐gp transport function. [ 30‐31 ] It was observed that 5 could effectively increase the intracellular accumulation of Rho‐123 and interrupt its efflux in HepG2/ADR cells (Figures 7b and 7d). This phenomenon was similar to the positive controls, two P‐gp inhibitors (verapamil and tariquidar), and the dose‐dependent manner of compound 5 was confirmed by flow cytometry analysis (Figure 7c).…”

Section: Resultsmentioning

confidence: 99%

“…All isolates were tested for their MDR reversal activity against two adriamycin (ADR) resistant cancer cell lines, HepG2/ADR or MCF‐7/ADR (Table 4). [ 30‐31 ] The MDR chemoreversal assay was performed by combining 20 μmol/L of tested compounds with 40 μmol/L of ADR. Then, the active compounds were screened for their cytotoxicity against HepG2/ADR and MCF‐7/ADR, and no obvious cytotoxicity of them towards tested cell lines was observed (IC 50 > 100 μmol/L), except for compounds 10 and 11 .…”

Section: Resultsmentioning

confidence: 99%

“…The mechanism for reversing P‐gp mediated MDR included two strategies, down‐ regulating the expression of P‐gp protein or the function‐blocking of P‐gp. [ 30‐31 ] Firstly, compound 5 was used to evaluate the inhibitory effect of P‐gp, however, no significant change of the protein was observed (Figure 7a). Then, the Rho‐123 accumulation assay was conducted to examine its influence of 5 on the P‐gp transport function.…”

Section: Resultsmentioning

confidence: 99%

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Hypermonones A—I, New Polyprenylated Acylphloroglucinols from Hypericum monogynum with Multidrug Resistance Reversal Activity

Zeng

Yang

et al. 2021

Chin. J. Chem.

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Main observation and conclusion Eleven biogenetically related polyprenylated acylphloroglucinols (PPAPs), including four novel skeletons (1—4) and five new compounds (5—9), were isolated from the flowers of Hypericum monogynum. Hypermonones A—D (1—4) represented the first example of a unique dilactone structure containing carbonyl bonded single δ‐lactone and tricyclic γ‐lactone moieties. Their structures were elucidated by NMR analysis, X‐ray crystallography, and ECD calculations. Moreover, we revised the structure of hyperibrin B to hypermonone I (9) via NMR analysis, a quantum computational chemistry method, and hypothetic biosynthetic considerations. Three compounds (5, 6, and 9) with significant MDR reversal activity (RF ranging from 61 to 223) were superior to the positive control verapamil (MCF‐7/ADR, RF: 53; HepG2/ADR, RF: 124). Mechanism study for compound 5 indicated that this compound could inhibit the function of P‐gp transport rather than its expression, and the possible recognition mechanism between compound 5 and P‐gp was predicted by molecular docking.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Hypermonones A—I, New Polyprenylated Acylphloroglucinols from Hypericum monogynum with Multidrug Resistance Reversal Activity

Zeng

Yang

et al. 2021

Chin. J. Chem.

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“…Most of the studied species contained both polycyclic and macrocyclic diterpenes and included E. lathyris [ 31 ], E. stracheyi [ 32 ], E. royleana [ 33 ], E. antiquorum [ 34 ], E. kansuensis [ 35 , 36 ], E. prolifera [ 37 ], E. peplus [ 38 ], E. aellenii [ 39 ], E. pilosa [ 40 ], E. saudiarabica [ 28 ], E. marginata [ 41 ], E. neriifolia [ 42 ], E. resinifera [ 43 ], E. pekinensis [ 44 ], E. hylonoma [ 45 ], E. milii [ 46 ], E. wallichii [ 47 ], and E. ebracteolata [ 48 ]. While others contained only macrocyclic diterpenes like E. esula [ 49 ], E. helioscopia [ 50 ], E. yinshanica [ 51 ], E. grandicornis [ 52 ], and E. kansui [ 53 ].…”

Section: Occurrence Of Euphorbia Diterpenesmentioning

confidence: 99%

Euphorbia Diterpenes: An Update of Isolation, Structure, Pharmacological Activities and Structure–Activity Relationship

et al. 2021

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Euphorbia species have a rich history of ethnomedicinal use and ethnopharmacological applications in drug discovery. This is due to the presence of a wide range of diterpenes exhibiting great structural diversity and pharmacological activities. As a result, Euphorbia diterpenes have remained the focus of drug discovery investigations from natural products. The current review documents over 350 diterpenes, isolated from Euphorbia species, their structures, classification, biosynthetic pathways, and their structure–activity relationships for the period covering 2013–2020. Among the isolated diterpenes, over 20 skeletal structures were identified. Lathyrane, jatrophane, ingenane, ingenol, and ingol were identified as the major diterpenes in most Euphorbia species. Most of the isolated diterpenes were evaluated for their cytotoxicity activities, multidrug resistance abilities, and inhibitory activities in vitro, and reported good activities with significant half-inhibitory concentration (IC50) values ranging from 10–50 µM. The lathyranes, isopimaranes, and jatrophanes diterpenes were further found to show potent inhibition of P-glycoprotein, which is known to confer drug resistance abilities in cells leading to decreased cytotoxic effects. Structure–activity relationship (SAR) studies revealed the significance of a free hydroxyl group at position C-3 in enhancing the anticancer and anti-inflammatory activities and the negative effect it has in position C-2. Esterification of this functionality, in selected diterpenes, was found to enhance these activities. Thus, Euphorbia diterpenes offer a valuable source of lead compounds that could be investigated further as potential candidates for drug discovery.

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“…Euri A was first isolated from Euphorbia neriifolia in 2014, 14 and was subsequently found to have anti-HIV and reverse tumor resistance effects. 15 At present, this compound has been able to achieve total synthesis. 16 Ingenane-type diterpenoids mainly existed in Euphorbia species , and the representative compound Ingenol 3-Angelate (PEP005) was found to have good antitumor activity and has been clinically used to treat actinic keratosis.…”

Section: Introductionmentioning

confidence: 99%

PKCδ/MAPKs and NF-κB Pathways are Involved in the Regulation of Ingenane-Type Diterpenoids from Euphorbia neriifolia on Macrophage Function

Jiang

Xue

et al. 2021

JIR

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Purpose Euphorbia neriifolia Linn. has important medicinal value in the treatment of ulcers, tumors, inflammation, chronic respiratory troubles, and so on. Although many ingredients with anti-inflammatory activity have been discovered and isolated from the Euphorbia neriifolia , the current research still cannot explain its multivariate effects on the immune response. This article aims to introduce two Ingenane-type diterpenoids from Euphorbia neriifolia with macrophage regulatory effects and to investigate the mechanism of their action. Methods The stem bark of E. neriifolia was extracted with various separation methods to obtain ingenane-type diterpenoids. The RAW264.7 cells were treated with lipopolysaccharide (LPS, 1 μg/mL) to establish an inflammatory cell model. The cell viability was detected by MTT assay. The secretion of PGE2, TNF-α, IL-1β, and IL-6 was tested with ELISA. The levels of iNOS, COX-2, IκBα, JNK, ERK, p38, p-IκBα, p-JNK, p-ERK, and p-p38 in cells were detected by Western blotting. The translocation of nuclear factor-kappa B (NF-κB)/p65 subunit were evaluated by Immunofluorescence staining. Results Ingenane-type diterpenoids, eurifoloid A (Euri A) and a new compound euphorneroid E (Euph E), were isolated from the EtOAc fraction of E. neriifolia stem bark extracts. Euph E and Euri A exhibited significant inhibition on the levels of pro-inflammatory mediators NO, IL-1β, IL-6, and iNOS on LPS-induced macrophage RAW264.7. Cellular signaling pathway studies showed that they prevented the degradation of IκBα and the translocation of NF-κB/p65 subunit. Furthermore, the production of PGE2, TNFα, and COX-2 was dramatically increased under the influence of the compounds, which were closely related to the phosphorylation of protein kinase C δ (PKCδ) and activation of mitogen-activated protein kinase (MAPKs) signaling pathway. Conclusion These results demonstrated that Euph E and Euri A exhibited multidirectional regulation on cytokines and immune function of macrophages, in addition to a good anti-inflammatory activity, and which was closely related to the regulation of PKCδ/MAPKs and NF-κB signal pathways.

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Diterpenoids from Euphorbia royleana reverse P-glycoprotein-mediated multidrug resistance in cancer cells

Cited by 29 publications

References 29 publications

Hypermonones A—I, New Polyprenylated Acylphloroglucinols from Hypericum monogynum with Multidrug Resistance Reversal Activity

Hypermonones A—I, New Polyprenylated Acylphloroglucinols from Hypericum monogynum with Multidrug Resistance Reversal Activity

Euphorbia Diterpenes: An Update of Isolation, Structure, Pharmacological Activities and Structure–Activity Relationship

PKCδ/MAPKs and NF-κB Pathways are Involved in the Regulation of Ingenane-Type Diterpenoids from Euphorbia neriifolia on Macrophage Function

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