A New Synthetic Ursolic Acid Derivative IUA with Anti-Tumor Efficacy Against Osteosarcoma Cells via Inhibition of JNK Signaling Pathway

Chen, Jian; Fu, Hai-Jian; Wang, Zhuoying; Yin, Fei; Li, Jianxin; Hua, Yingqi; Cai, Zhengdong

doi:10.1159/000363037

Cited by 12 publications

(12 citation statements)

References 32 publications

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“…This result indicates that the modification at C-28 and 3-OH in the UA core significantly increases the antitumor activities of UA. These results are consistent with a previous study by Chen et al ( 36 ), which demonstrated that the structural changes in position 3 and/or 28 of UA were crucial for its cytotoxic activity. In another study, UA-benzylidine derivatives exhibited strong cytotoxic activity and amino acid linkage ( 37 ), and UA also caused significant cytotoxic effects in different cancer cell lines.…”

Section: Discussionsupporting

confidence: 93%

A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines

Zhang

Nie

et al. 2017

Oncol Lett

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The present study investigated the anticancer functions of ursolic acid (UA) and its novel derivatives, with a nitrogen-containing heterocyclic scaffold and the privileged fragment at the C-28 position on apoptosis induction, cell proliferation and cell cycle in human BC lines. UA was chemically modified in the present study to increase its antitumor activity and bioavailability. A novel UA derivative, FZU3010, was synthesized using a nitrogen-containing heterocyclic scaffold and a privileged fragment at the C-28 position. Sulforhodimine B assays were used to measure the effect of UA and different concentrations of FZU3010 on the viability of breast cancer (BC) SUM149PT and HCC1937 cells. FZU3010 significantly repressed the proliferation of the two cancer cell lines in a dose-dependent manner, with a half-maximal inhibitory concentration of 4–6 µM, and exhibited decreased cytotoxicity compared with vehicle-treated cell lines. The effect of FZU3010 on cell cycle distribution and cellular apoptosis was also investigated. The results of this investigation indicated that FZU3010 significantly increased the number of SUM149PT and breast cancer HCC1937 cells in the G0/G1 phase in a dose-dependent manner. Additionally, at a concentration of 5 µM, the capability of FZU3010 to induce BC apoptosis was significantly higher than the capability of UA. Thus, the results of the current study indicated that FZU3010 induced apoptosis in BC cells, together with induction of cell cycle arrest at the S and G0/G1 phase. FZU3010 may therefore be considered as a potential therapeutic agent for the treatment of BC.

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Section: Discussionsupporting

confidence: 93%

A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines

Zhang

Nie

et al. 2017

Oncol Lett

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“…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). However, the antitumor activity of ursolic acid derivatives in oral cancers has been rarely reported.…”

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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“…To further investigate the inhibitory activity of the leading compound 5b, we evaluated the proliferation inhibition effect of 5b against some other different cancer cell lines. The proliferation inhibition ability of 5b on MCF-7, MDA-MB-231, HT-29, LoVo, B16-F10, RL95-2, and SCL-1 cell lines was tested by MTT assay at different concentrations (1,5,10,20, and 40 lM) for 24 h. Compound 5b showed decreased cell viability in a dose-dependent manner. The IC 50 values of 5b against these cell lines were 7.05, 5.71, 9.40, 7.78, 6.79, 6.87, and 7.13 lM, respectively ( Table 2).…”

Section: Effect Of Ua-5b On Cell Viabilitymentioning

confidence: 99%

“…To improve its activity and bioavailability, structural modifications were performed on UA to discover potential anticancer agents . It has been reported that some of UA derivatives that modified at the 3‐OH and/or 17‐COOH positions exhibit significant antitumor effects both in vitro and in vivo . Previous studies in our laboratory showed that incorporation of N ‐(2‐hydroxyethyl) piperazine or 2‐methylpiperazine moiety at the C‐28 position of UA exhibited better inhibitory effect on growth of cancer cells .…”

mentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs

Yang

Jiang

et al. 2015

Chem Biol Drug Des

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Ursolic acid (UA) is a natural product which has been shown to possess a wide range of pharmacological activities, in particular those with anticancer activity. In this study, 13 novel ursolic acid derivatives were designed and synthesized in an attempt to further improve compound potency. The structures of the newly synthesized compounds were confirmed using mass spectrometry, infrared spectroscopy, and (1) H NMR. The ability of the UA derivatives to inhibit cell growth was assayed against both various tumor cell lines and a non-pathogenic cell line, HELF. Analysis of theoretical toxicity risks for all derivatives was performed using OSIRIS and indicated that the majority of compounds would present moderate to low risks. Pharmacological results indicated that the majority of the derivatives were more potent growth inhibitors than UA. In particular, 5b demonstrated IC50 values ranging from 4.09 ± 0.27 to 7.78 ± 0.43 μm against 12 different tumor cell lines. Flow cytometry analysis indicated that 5b induced G0/G1 arrest in three of these cell lines. These results were validated by structural docking studies, which confirmed that UA could bind to cyclins D1 (Cyc D1) and cyclin-dependent kinases (CDK6), the key regulators of G0/G1 transition in cell cycle, while the piperazine moiety of 5b could bind with glucokinase (GK), glucose transporter 1 (GLUT1), and ATPase, which are the main proteins involved in cancer cell metabolism. Acridine orange/ethidium bromide staining confirmed that 5b was capable of inducing apoptosis and decreasing cell viability in a dose-dependent manner.

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A New Synthetic Ursolic Acid Derivative IUA with Anti-Tumor Efficacy Against Osteosarcoma Cells via Inhibition of JNK Signaling Pathway

Cited by 12 publications

References 32 publications

A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines

A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines

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

Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs

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