Cytotoxic coumarins and lignans from extracts of the northern prickly ash (<i>Zanthoxylum americanum</i>)

Ju, Yi‐Hsu; Still, Cecil C.; Sacalis, John N.; Li, Jiangang; Ho, Chi‐Tang

doi:10.1002/ptr.686

Cited by 59 publications

(43 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Here we provide evidence showing that ())-sesamin-induced G 1 phase arrest is triggered by DNA DSBs. Interestingly, several coumarin and lignan derivatives including sesamin and asarinin inhibited DNA synthesis in human leukemia HL-60 cells, (42) both of which are potent inhibitors of Lon protease ( (44) and this work). Double-strand breaks are the most cytotoxic DNA lesions and activate the DNA damage response, which determine cell fate such as cell cycle arrest, repair, or apoptosis.…”

Section: Discussionmentioning

confidence: 64%

Obtusilactone A and (−)‐sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints

et al. 2010

View full text Add to dashboard Cite

Several compounds from Cinnamomum kotoense show anticancer activities. However, the detailed mechanisms of most compounds from C. kotoense remain unknown. In this study, we investigated the anticancer activity of obtusilactone A (OA) and ())-sesamin in lung cancer. Our results show that human Lon is upregulated in non-small-cell lung cancer (NSCLC) cell lines, and downregulation of Lon triggers caspase-3 mediated apoptosis. Through enzymebased screening, we identified two small-molecule compounds, obtusilactone A (OA) and ())-sesamin from C. kotoense, as potent Lon protease inhibitors. Obtusilactone A and ())-sesamin interact with Ser855 and Lys898 residues in the active site of the Lon protease according to molecular docking analysis. Thus, we suggest that cancer cytotoxicity of the compounds is partly due to the inhibitory effects on Lon protease. In addition, the compounds are able to cause DNA double-strand breaks and activate checkpoints. Treatment with OA and ())-sesamin induced p53-independent DNA damage responses in NSCLC cells, including G 1 ⁄ S checkpoint activation and apoptosis, as evidenced by phosphorylation of checkpoint proteins (H2AX, Nbs1, and Chk2), caspase-3 cleavage, and sub-G 1 accumulation. In conclusion, OA and ())-sesamin act as both inhibitors of human mitochondrial Lon protease and DNA damage agents to activate the DNA damage checkpoints as well induce apoptosis in NSCLC cells. These dual functions open a bright avenue to develop more selective chemotherapy agents to overcome chemoresistance and sensitize cancer cells to other chemotherapeutics. (Cancer Sci 2010; 101: 2612-2620 L ung cancer is a leading cause of cancer-related death in both men and women in the USA (1) and Taiwan. The survival rate after chemotherapy regimens and the drug development of molecular-targeted agents for lung cancer therapy is still challenging. (2,3) Lon is a highly conserved ATP-dependent serine protease that has been identified from prokaryotes and to mitochondria of eukaryotes.(4) In vivo studies show that Lon plays an important role in mitochondrial DNA maintenance and expression (5)(6)(7) and regulation of mitochondria function.(8) Mitochondrial function is a crucial determinant of cellular sensitivity to cancer therapeutic drugs because of its roles in mediating apoptosis.(9) Enhanced mitochondrial biogenesis as well as tumorigenesis are linked to overexpression and increased proteolytic activity of Lon. (8,10) Downregulation of Lon leads to loss of mitochondrial function, reduced cell proliferation capacity, and apoptosis. (11,12) Deregulation of Lon leading to tumorigenesis has raised its potential as a target in the development of a novel drug in cancer therapy.To date, very few small-molecule inhibitors of Lon protease have been found, although several peptide-based proteasome inhibitors have been reported. (13,14) Cell cycle checkpoints are sophisticated surveillance mechanisms that are used to monitor the integrity of DNA.(15,16) After DNA lesions are sensed by sensor proteins, the kinase activ...

show abstract

Section: Discussionmentioning

confidence: 64%

Obtusilactone A and (−)‐sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Ju and co-workers reported that 5 inhibited the incorporation of tritiated thymidine into human leukemia (HL-60) cells, which means that it inhibited DNA synthesis. They indicated that the 50% inhibition concentration (IC 50 ) of 5 is 3.48 ppm (15.28 lM) [21], and this was one of a range of concentrations we examined. Although the cell line was certainly different, it is possible that xanthoxyletin could exert a certain action on the gene constructional system, and it is suggested that this could have caused the suppression of iNOS expression.…”

Section: Resultsmentioning

confidence: 99%

Inhibitory effect of oxycoumarins isolated from the Thai medicinal plant Clausena guillauminii on the inflammation mediators, iNOS, TNF-α, and COX-2 expression in mouse macrophage RAW 264.7

et al. 2008

View full text Add to dashboard Cite

In the present study, we investigated the inhibitory effect of the known oxycoumarins poncitrin (3), osthol (4), and xanthoxyletin (5), newly isolated from Clausena guillauminii (Rutaceae), together with the known carbazoles heptaphylline (1) and 7-methoxyheptaphylline (2) on inducible-nitric oxide synthase (iNOS) expression induced by lipopolysaccharide (LPS) and the NO generation in RAW 264.7 mouse macrophages. Isolation of active oxycoumarins was guided by Western blot analysis of iNOS protein expression. These oxycoumarins showed an inhibitory effect on iNOS protein expression at 10 microM. Further examination of the inhibitory effects of these compounds on inflammation mediators revealed that the synthesis of nitric oxide (NO) and the protein expression of tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) were inhibited by 5. It was expected that these compounds show anti-inflammatory activities.

show abstract

“…Islam et al (2001) verified that etheric extracts from the bark of Z. rhesta are toxic to Artemia salina which, on the other hand, does not suffer toxic action from chlorophormic extracts of Z. budrunga; Ju et al (2001) showed that Z. americanum presented substances, as dipetaline, alloxanthoxyletin e sesamin, that inhibit the DNA synthesis in HL-60 cells; Rodrigues et al (1998) reported the hexane extracts of Z. naranjillo induced alterations in albumin and alkaline phosphatase levels in mice, without liver or biliary alterations, which suggests a possible absence of clinical toxicity. From these studies, it is possible to confirm several potential therapeutical uses of plants from the genus Zanthoxylum.…”

Section: Introductionmentioning

confidence: 94%

Cytotoxic evaluation of essential oil from Zanthoxylum rhoifolium Lam. leaves

2007

View full text Add to dashboard Cite

Zanthoxylum rhoifolium Lam is a plant popularly used as antimicrobial, for malaria and inflammatory treatment. The essential oil of Z. rhoifolium was extracted and its cytotoxic effects against HeLa (human cervical carcinoma), A-549 (human lung carcinoma), HT-29 (human colon adenocarcinoma), Vero (monkey kidney) cell lines and mice macrophages were evaluated. Some of the terpenes of its essential oil (β-caryophyllene, α-humulene, α-pinene, myrcene and linalool) were also tested to verify their possible influence in the oil cytotoxic activity. The results obtained permitted to confirm that the essential oil is cytotoxic against tumoral cells (CD 50 = 82.3, 90.7 and 113.6 µg/ml for A-549, HeLa e HT-29 cell lines, respectively), while it did not show cytotoxicity against non-tumoral cells (Vero and mice macrophages). Thus, the essential oil from Z. rhoifolium leaves seems to present a possible therapeuthic role due to its selective cytotoxic activity against tumoral cell lines. KEYWORDSZanthoxylum, Essential oil, cytotoxicity, β-caryophyllene, α-humulene Avaliação citotóxica do óleo volátil extraído das folhas do

show abstract

Cytotoxic coumarins and lignans from extracts of the northern prickly ash (Zanthoxylum americanum)

Cited by 59 publications

References 9 publications

Obtusilactone A and (−)‐sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints

Obtusilactone A and (−)‐sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints

Inhibitory effect of oxycoumarins isolated from the Thai medicinal plant Clausena guillauminii on the inflammation mediators, iNOS, TNF-α, and COX-2 expression in mouse macrophage RAW 264.7

Cytotoxic evaluation of essential oil from Zanthoxylum rhoifolium Lam. leaves

Contact Info

Product

Resources

About