Betulinic Acid Exerts Cytotoxic Activity Against Multidrug-Resistant Tumor Cells via Targeting Autocrine Motility Factor Receptor (AMFR)

Saeed, Mohamed E.M.; Mahmoud, Nuha; Sugimoto, Yoshikazu; Efferth, Thomas; Abdel-Aziz, H

doi:10.3389/fphar.2018.00481

Cited by 39 publications

(28 citation statements)

References 56 publications

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“…In addition, a study reported that betulinic acid decreases the growth of estrogen receptor (ER)-negative MDA-MB-231 breast cancer cells in vitro and in vivo by interactions with the microRNA-27a-ZBTB10-Sp-axis, causing increased cell death [48]. Furthermore, betulinic acid has been reported to exert cytotoxic activity against multidrug-resistant tumor cells by targeting autocrine motility factor receptor (AMFR), which is a ubiquitin E3-ligase cell surface glycoprotein that is known to play a role in metastasis, tumor progression, and recurrence [49]. Interestingly, a synergistic effect was observed in the anticancer activity when betulinic acid was used in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or ionizing radiation [50,51].…”

Section: Resultsmentioning

confidence: 99%

Betulinic Acid Suppresses Ovarian Cancer Cell Proliferation through Induction of Apoptosis

Lee

Kang

et al. 2019

Biomolecules

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Ovarian cancer is one of the leading causes of cancer deaths worldwide in women, and the most malignant cancer among the different gynecological cancers. In this study, we explored potentially anticancer compounds from Cornus walteri (Cornaceae), the MeOH extract of which has been reported to show considerable cytotoxicity against several cancer cell lines. Phytochemical investigations of the MeOH extract of the stem and stem bark of C. walteri by extensive application of chromatographic techniques resulted in the isolation of 14 compounds (1–14). The isolated compounds were evaluated for inhibitory effects on the viability of A2780 human ovarian carcinoma cells and the underlying molecular mechanisms were investigated. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was employed to assess the anticancer effects of compounds 1–14 on A2780 cells, which showed that compound 11 (betulinic acid) reduced the viability of these cells in a concentration-dependent manner and had an half maximal (50%) inhibitory concentration (IC50) of 44.47 μM at 24 h. Nuclear staining and image-based cytometric assay were carried out to detect the induction of apoptosis by betulinic acid. Betulinic acid significantly increased the condensation of nuclei and the percentage of apoptotic cells in a concentration-dependent manner in A2780 cells. Western blot analysis was performed to investigate the underlying mechanism of apoptosis. The results indicated that the expression levels of cleaved caspase-8, -3, -9, and Bax were increased in A2780 cells treated with betulinic acid, whereas those of Bcl-2 were decreased. Thus, we provide the experimental evidence that betulinic acid can induce apoptosis in A2780 cells through both mitochondria-dependent and -independent pathways and suggest the potential use of betulinic acid in the development of novel chemotherapeutics for ovarian cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Betulinic Acid Suppresses Ovarian Cancer Cell Proliferation through Induction of Apoptosis

Lee

Kang

et al. 2019

Biomolecules

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“…recorded upon treatments with DCB, compounds 1 , 3, and 4 were lower than with doxorubicin (Table 1). Previous studies also reported the hypersensitivity of CEM/ADR5000 leukemia cells to compound 1 as compared to its sensitive congener CCRF-CEM cells [34]. These data are indications that Dichrostachys cinerea and its constituents have the potential to combat cancer multidrug resistance.…”

Section: Discussionmentioning

confidence: 63%

“…However, preliminary antiproliferative effects of this plant were reported towards DU145 and 22Rv1 prostate cancer cells and HeLa cervical cancer cells, with the lowest IC 50 values of 8.04 μ g/ml recorded in 22Rv1 cells [7]. Also, betulinic acid is a well-known cytotoxic compound [34]. Its effects have been reported towards several cancer cell lines including sensitive and resistant phenotypes such as CCRF-CEM cells and CEM/ADR5000 leukemia cells, MDA-MB-231-pcDNA and MDA-MB-231/ BCRP breast adenocarcinoma cells, HEK293 and HEK293/ ABCB5 embryonic kidney cells, and U87.MG and U87.MG ΔEGFR glioblastoma cells with IC 50 values ranging from 15.1 μ M (against HEK293 cells) to 29.4 μ M (towards CCRF-CEM cells) [34, 36].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies on the molecular mechanism of the cytotoxic action of compound 1 showed that it inhibited P-gp, BCRP, and ABCB5 and mutation activated EGFR overexpressing cells. Besides, various genes significantly correlated to its activity on cell cycle regulation, microtubule formation, signal transduction, transcriptional regulation, chromatin remodeling, cell adhesion, tumor suppression, ubiquitination, and proteasome degradation [34].…”

Section: Discussionmentioning

confidence: 99%

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Cytotoxicity of Crude Extract and Isolated Constituents of theDichrostachys cinereaBark towards Multifactorial Drug-Resistant Cancer Cells

Mbaveng

Damen

Mpetga

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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The effectiveness of anticancer chemotherapy is greatly impeded by the resistance of malignant cells to cytotoxic drugs. In this study, the cytotoxicity of the crude extract (DCB) and compounds isolated from the bark of Dichrostachys cinerea, namely, betulinic acid (1), glyceryl-1-hexacosanoate (2), 7-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (3), and 6-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (4), was investigated. The study was extended to the assessment of the mode of induction of apoptosis by DCB and compound 1. The resazurin reduction assay was used for cytotoxicity studies. Assessments of cell cycle distribution, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were performed by flow cytometry. Constituents of DCB were isolated by column chromatography. Triterpenoid 1 and flavone 4 had cytotoxic effects towards the 9 tested cancer cell lines with IC50 values below 50 μM. The recorded IC50 values varied from 7.65 μM (towards multidrug-resistant CEM-ADR5000 leukemia cells) to 44.17 μM (against HepG2 hepatocarcinoma cells) for 1, 18.90 μM (CCRF-CEM leukemia cells) to 88.86 μM (against HCT116p53+/+ colon adenocarcinoma cells) for 4, and 0.02 μM (against CCRF-CEM cells) to 122.96 μM (against CEM/ADR5000 cells) for doxorubicin. DCB induced apoptosis in CCRF-CEM cells mostly mediated by MMP alteration and enhanced ROS production; compound 1 induced apoptosis through caspases activation and MMP alteration and increased ROS production. Dichrostachys cinerea is an interesting cytotoxic plant and deserves more studies leading to new antineoplastic agents to fight cancer and mostly leukemia.

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“…Synthesis usually takes three or more stages with a maximum betulinic acid yield of 55% [1]. BA has a wide range of anti-tumor effects and exhibits anti-HIV activity [2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Search for a Source of Triterpene Acids in Russian Birches

Vedernikov

Eregina

Shemyakina

2020

JCPRM

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The composition of triterpene acids and triterpene alcohols of the outer bark of a damaged silver birch tree (Betula pendula Roth.) the outer bark of silver birch branches, the outer bark of Betula davurica Pall., B. mandshurica (Regel) Nakai, B. platyphylla Sucacz. and B. costata Trautv. is considered. Silver birch bark was harvested in the Leningrad region. The bark of other species of birches was harvested in the Khabarovsk region. The qualitative composition of triterpene compounds was determined by chromatography-mass spectrometry. The quantitative composition was determined by gas-liquid chromatography and absolute calibration. Butyl esters of acids were preliminarily prepared for GLC analysis of triterpene acids. The outer bark of the eastern species of birches contains significantly more betulinic and oleanolic acid than silver birch. The relative content of triterpene acids is greater in the outer bark of branches and in the bark of damaged silver birches. The increase in acid content is apparently associated with the desire to heal a wound. The main component among the triterpenoids of the investigated raw materials is betulin. For the separation of acids from other triterpenoids, various solubilities of the compounds in solvents and the ability of acids to form poorly soluble salts were used.

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Betulinic Acid Exerts Cytotoxic Activity Against Multidrug-Resistant Tumor Cells via Targeting Autocrine Motility Factor Receptor (AMFR)

Cited by 39 publications

References 56 publications

Betulinic Acid Suppresses Ovarian Cancer Cell Proliferation through Induction of Apoptosis

Betulinic Acid Suppresses Ovarian Cancer Cell Proliferation through Induction of Apoptosis

Cytotoxicity of Crude Extract and Isolated Constituents of theDichrostachys cinereaBark towards Multifactorial Drug-Resistant Cancer Cells

Search for a Source of Triterpene Acids in Russian Birches

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