Anti-Proliferative effect of ursolic acid on multidrug resistant hepatoma cells R-HepG2 by apoptosis induction

Zhang, Dongmei; Tang, Patrick Ming‐Kuen; Chan, Judy Yuet-Wa; Lam, Hung‐Ming; Au, Shannon Wing-Ngor; Kong, Siu‐Kai; Tsui, Stephen Kwok-Wing; Waye, Mary Mui-Yee; Mak, Thomas C. W.; Fung, Kai-hung

doi:10.4161/cbt.6.9.4528

Cited by 12 publications

(9 citation statements)

References 18 publications

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“…The three plant extracts, the root extracts of Glycyrrhiza glabra , Paeonia lactiflora , and the leaf extract of Eriobotrya japonica possess moderate cytotoxic properties which agrees with published data [27,38,58,59,60]. So do the six PSM [30,31,34,35,36,37,38,39,40,44,46,47], which are major PSM in these TCM plants (Table 2). Only ursolic acid showed IC 50 values below 20 µM.…”

Section: Discussionsupporting

confidence: 88%

“…Ursolic acid (urs) circumvented MDR in human hepatoma cell line R-HepG2 through apoptosis induction but not through P-gp inhibition [46]; ursolic acid increased rhodamine 123 retention in a concentration-dependent manner via inhibiting P-gp in KB-C2 cells [47]. Here, ursolic acid synergistically sensitised both CEM/ADR5000 and Caco-2 cells to doxorubicin by inhibiting ABC transporter activity and expression and interfering with apoptosis- and metabolism-related enzyme expressions.…”

Section: Discussionmentioning

confidence: 99%

“…Paeoniflorin exhibits anti-inflammatory, immunoregulatory, neuroprotective, and anti-cancer properties [41,42,43,44]. Ursolic acid, a pentacyclic triterpenoid in E. japonica and widely distributed in various plants [45], has a wide spectrum of pharmacological activities, for example, antimutagenic, and anti-cancer activities [46,47]. The structures of the compounds are shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

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Reversal of Multidrug Resistance in Human Colon Cancer and Human Leukemia Cells by Three Plant Extracts and Their Major Secondary Metabolites

Zhou

2018

Medicines

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Background: We studied the effect of three plant extracts (Glycyrrhiza glabra, Paeonia lactiflora, Eriobotrya japonica) and six of their major secondary metabolites (glycyrrhizic acid, 18β glycyrrhetinic acid, liquiritigenin, isoliquiritigenin, paeoniflorin, ursolic acid) on the multidrug resistant human colon cancer cell line Caco-2 and human leukemia cell line CEM/ADR 5000 as compared to the corresponding sensitive cell line CCRF-CEM, and human colon cancer cells HCT-116, which do not over-express ATP-binding cassette (ABC) transporters. Methods: The cytotoxicity of single substances in sensitive and resistant cells was investigated by MTT assay. We also applied combinations of extracts or single compounds with the chemotherapeutic agent doxorubicin or doxorubicin plus the saponin digitonin. The intracellular retention of the ABC transporter substrates rhodamine 123 and calcein was examined by flow cytometry to explore the effect of the substances on the activity of ABC transporters P-glycoprotein and MRP1. Real-time PCR was applied to analyse the gene expression changes of ABCB1, ABCC1, caspase 3, caspase 8, AhR, CYP1A1, and GSTP1 in resistant cells under the treatment of the substances. Results: All the substances moderately inhibited cell growth in sensitive and resistant cells to some degree. Whereas ursolic acid showed IC50 of 14 and 22 µM in CEM/ADR 5000 and Caco-2 cells, respectively, glycyrrhizic acid and paeoniflorin were inactive with IC50 values above 400 μM. Except for liquiritigenin and isoliquiritigenin, all the other substances reversed MDR in CEM/ADR 5000 and Caco-2 cells to doxorubicin. Ue, ga, 18ga, and urs were powerful reversal agents. In CEM/ADR 5000 cells, high concentrations of all the substances, except Paeonia lactiflora extract, increased calcein or rhodamine 123 retention in a dose-dependent manner. In Caco-2 cells, all the substances, except liquiritigenin, retained rhodamine 123 in a dose-dependent manner. We also examined the effect of the plant secondary metabolite (PSM) panel on the expression of ABCB1, ABCC1, caspase 3, caspase 8, AhR, CYP1A1, and GSTP1 genes in MDR cells. Conclusions: The extracts and individual PSM could reverse MDR in CEM/ADR 5000 and Caco-2 cells, which overexpress ABC transporters, in two- and three-drug combinations. Most of the PSM also inhibited the activity of ABC transporters to some degree, albeit at high concentrations. Ue, ga, 18ga, and urs were identified as potential multidrug resistance (MDR) modulator candidates, which need to be characterized and validated in further studies.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reversal of Multidrug Resistance in Human Colon Cancer and Human Leukemia Cells by Three Plant Extracts and Their Major Secondary Metabolites

Zhou

2018

Medicines

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“…Ursolic acid (UA) is an attractive compound with potent anticancer activity in several types of cancers such as melanoma, leukemia, colorectal, lung, and breast cancers (Cai et al ., 2017). Ursolic acid displays various anticancer actions by reducing oncogene expression, modulating cell cycle, triggering apoptosis, suppressing metastasis, and regulating drug resistance (Zhang et al ., 2007; Manu and Kuttan, 2008; Lin et al ., 2013; Ou et al ., 2014; Xiang et al ., 2015). Ursolic acid derivatives such as FZU-03,010, ursolic acid-benzylidine, UP12, and IUA have been demonstrated as potent anticancer agents against hepatocellular carcinoma, osteosarcoma, lung, colon, and breast cancer cells (Chen et al ., 2014; Dong et al ., 2015; Dar et al ., 2016; Li et al ., 2017).…”

Section: Introductionmentioning

confidence: 99%

Cis-3-O-p-hydroxycinnamoyl Ursolic Acid Induced ROS-Dependent p53-Mediated Mitochondrial Apoptosis in Oral Cancer Cells

Lin

Hua

Jou

et al. 2019

Biomolecules & Therapeutics

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Cis-3-O-p-hydroxycinnamoyl ursolic acid (HCUA), a triterpenoid compound, was purified from Elaeagnus oldhamii Maxim. This traditional medicinal plant has been used for treating rheumatoid arthritis and lung disorders as well as for its anti-inflammation and anticancer activities. This study aimed to investigate the anti-proliferative and apoptotic-inducing activities of HCUA in oral cancer cells. HCUA exhibited anti-proliferative activity in oral cancer cell lines (Ca9-22 and SAS cells), but not in normal oral fibroblasts. The inhibitory concentration of HCUA that resulted in 50% viability was 24.0 µM and 17.8 µM for Ca9-22 and SAS cells, respectively. Moreover, HCUA increased the number of cells in the sub-G1 arrest phase and apoptosis in a concentration-dependent manner in both oral cancer cell lines, but not in normal oral fibroblasts. Importantly, HCUA induced p53-mediated transcriptional regulation of pro-apoptotic proteins (Bax, Bak, Bim, Noxa, and PUMA), which are associated with mitochondrial apoptosis in oral cancer cells via the loss of mitochondrial membrane potential. HCUA triggered the production of intracellular reactive oxygen species (ROS) that was ascertained to be involved in HCUA-induced apoptosis by the ROS inhibitors YCG063 and N-acetyl-L-cysteine. As a result, HCUA had potential antitumor activity to oral cancer cells through eliciting ROS-dependent and p53-mediated mitochondrial apoptosis. Overall, HCUA could be applicable for the development of anticancer agents against human oral cancer.

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“…17 These properties give UA the potential to become an effective anticancer agent. However, because traditional analytical means have provided only a limited understanding of the underlying mechanisms, the anticancer properties of UA and its interactions with target-related protein during CRC are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Comparative proteomics—network analysis of proteins responsible for ursolic acid–induced cytotoxicity in colorectal cancer cells

et al. 2017

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Ursolic acid is a key active compound present in many medicinal herbs that have been widely used in traditional Chinese medicine for the clinical treatment of various cancers. However, the precise mechanisms of its antitumor activity have been poorly understood. To identify the cellular targets of ursolic acid, two-dimensional gel electrophoresis combined with mass spectrometry was performed in this study, which identified 15 proteins with significantly altered levels in protein expression. This demonstrated that ursolic acid-induced cytotoxicity in colorectal cancer cells involves dysregulation in protein folding, signal transduction, cell proliferation, cell cycle, and apoptosis. Corresponding protein regulation was also confirmed by Western blotting. Furthermore, the study of functional association between these 15 proteins revealed that 10 were closely related in a protein-protein interaction network, whereby the proteins either had a direct interaction with each other or were associated via only one intermediary protein. In this instance, the ATP5B/ CALR/HSP90B1/HSPB1/HSPD1-signaling network was revealed as the predominant target which was associated with the majority of the observed protein-protein interactions. As a result, the identified targets may be useful in explaining the anticancer mechanisms of ursolic acid and as potential targets for colorectal cancer therapy.

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Anti-Proliferative effect of ursolic acid on multidrug resistant hepatoma cells R-HepG2 by apoptosis induction

Cited by 12 publications

References 18 publications

Reversal of Multidrug Resistance in Human Colon Cancer and Human Leukemia Cells by Three Plant Extracts and Their Major Secondary Metabolites

Reversal of Multidrug Resistance in Human Colon Cancer and Human Leukemia Cells by Three Plant Extracts and Their Major Secondary Metabolites

Cis-3-O-p-hydroxycinnamoyl Ursolic Acid Induced ROS-Dependent p53-Mediated Mitochondrial Apoptosis in Oral Cancer Cells

Comparative proteomics—network analysis of proteins responsible for ursolic acid–induced cytotoxicity in colorectal cancer cells

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