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A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis.

Xiang L, Chi T, Tang Q, Yang X, Ou M, Chen X, Yu X, Chen J, Ho RJ, Shao J, Jia L - Oncotarget (2015)

Bottom Line: Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis.We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities.Thus, UA and US597 are potential drug candidates for preventing cancer metastasis.

View Article: PubMed Central - PubMed

Affiliation: Cancer Metastasis Alert and Prevention Center and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou 350002, China.

ABSTRACT
Here we showed that ursolic acid (UA), a pentacyclic triterpene natural product, and its novel prodrug derivative US597 suppressed cancer cells adhesion, invasion and migration. This effect was accompanied by inhibition of focal adhesion signaling pathway including alterations in ICAM-1, VCAM-1, E-selectin, P-selectin, integrin α6β1, FAK, Src, paxillin and PTEN. While oral administration of UA or US597 increases survival rate of melanoma lung metastasis in C57BL/6 mice, US597 treatment extend the survival rate above that of UA. Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis. We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities. Thus, UA and US597 are potential drug candidates for preventing cancer metastasis. Molecular and cellular study data suggest that UA and US597 modulate expression of cell adhesion molecules within focal adhesion signaling pathway leading to cancer cell motility.

No MeSH data available.


Related in: MedlinePlus

(A) Hierarchical clustering of the gene expression profiles of focal adhesion genes(B) Comparison of the expression levels of genes as fold-changes between the control group and the UA/US597 treated group by qRT-PCR. Data were normalized using β-actin as an endogenous control for RNA input. Fold-changes for these mRNAs from the qRT-PCR are shown as mean ± SD. (n = 3 for each group, *P < 0.05 and **P < 0.01). (C) UA is docked into the active site of FAK, showing interactions between UA and FAK by using the in silico model. (D) A 2-dimensional interaction map of UA and FAK.
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Figure 4: (A) Hierarchical clustering of the gene expression profiles of focal adhesion genes(B) Comparison of the expression levels of genes as fold-changes between the control group and the UA/US597 treated group by qRT-PCR. Data were normalized using β-actin as an endogenous control for RNA input. Fold-changes for these mRNAs from the qRT-PCR are shown as mean ± SD. (n = 3 for each group, *P < 0.05 and **P < 0.01). (C) UA is docked into the active site of FAK, showing interactions between UA and FAK by using the in silico model. (D) A 2-dimensional interaction map of UA and FAK.

Mentions: Considering the facts that UAs have been used in the treatment of liver diseases [24], and hepatocellular carcinoma cell line HepG2 also shows better sensitivity to UA/US597 in vitro, we decided to focus on HepG2 cell line for the further underlying mechanism study. To further assess the expression pattern of the genes after HepG2 cells were treated with US597 (5 μM, 24 h), the microarray analysis were performed using an Affymetrix human U133plus 2.0 array. The microarray data showed that the expressions of 720 genes were significantly altered (≥ 1.5 fold change plus corrected t-test p-value < 0.1): 498 genes were up-regulated and 252 genes were down-regulated (Supplementary Figure S2A, n = 3). As indicated in Supplementary Figure S2B, these genes are mostly associated with cell proliferation, apoptosis, adhesion and signal transduction in response to US597 treatment. More importantly, 13 genes were involved in the focal adhesion signaling pathway—the key signaling pathway associated with cancer metastasis (Figure 4A).


A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis.

Xiang L, Chi T, Tang Q, Yang X, Ou M, Chen X, Yu X, Chen J, Ho RJ, Shao J, Jia L - Oncotarget (2015)

(A) Hierarchical clustering of the gene expression profiles of focal adhesion genes(B) Comparison of the expression levels of genes as fold-changes between the control group and the UA/US597 treated group by qRT-PCR. Data were normalized using β-actin as an endogenous control for RNA input. Fold-changes for these mRNAs from the qRT-PCR are shown as mean ± SD. (n = 3 for each group, *P < 0.05 and **P < 0.01). (C) UA is docked into the active site of FAK, showing interactions between UA and FAK by using the in silico model. (D) A 2-dimensional interaction map of UA and FAK.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496218&req=5

Figure 4: (A) Hierarchical clustering of the gene expression profiles of focal adhesion genes(B) Comparison of the expression levels of genes as fold-changes between the control group and the UA/US597 treated group by qRT-PCR. Data were normalized using β-actin as an endogenous control for RNA input. Fold-changes for these mRNAs from the qRT-PCR are shown as mean ± SD. (n = 3 for each group, *P < 0.05 and **P < 0.01). (C) UA is docked into the active site of FAK, showing interactions between UA and FAK by using the in silico model. (D) A 2-dimensional interaction map of UA and FAK.
Mentions: Considering the facts that UAs have been used in the treatment of liver diseases [24], and hepatocellular carcinoma cell line HepG2 also shows better sensitivity to UA/US597 in vitro, we decided to focus on HepG2 cell line for the further underlying mechanism study. To further assess the expression pattern of the genes after HepG2 cells were treated with US597 (5 μM, 24 h), the microarray analysis were performed using an Affymetrix human U133plus 2.0 array. The microarray data showed that the expressions of 720 genes were significantly altered (≥ 1.5 fold change plus corrected t-test p-value < 0.1): 498 genes were up-regulated and 252 genes were down-regulated (Supplementary Figure S2A, n = 3). As indicated in Supplementary Figure S2B, these genes are mostly associated with cell proliferation, apoptosis, adhesion and signal transduction in response to US597 treatment. More importantly, 13 genes were involved in the focal adhesion signaling pathway—the key signaling pathway associated with cancer metastasis (Figure 4A).

Bottom Line: Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis.We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities.Thus, UA and US597 are potential drug candidates for preventing cancer metastasis.

View Article: PubMed Central - PubMed

Affiliation: Cancer Metastasis Alert and Prevention Center and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou 350002, China.

ABSTRACT
Here we showed that ursolic acid (UA), a pentacyclic triterpene natural product, and its novel prodrug derivative US597 suppressed cancer cells adhesion, invasion and migration. This effect was accompanied by inhibition of focal adhesion signaling pathway including alterations in ICAM-1, VCAM-1, E-selectin, P-selectin, integrin α6β1, FAK, Src, paxillin and PTEN. While oral administration of UA or US597 increases survival rate of melanoma lung metastasis in C57BL/6 mice, US597 treatment extend the survival rate above that of UA. Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis. We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities. Thus, UA and US597 are potential drug candidates for preventing cancer metastasis. Molecular and cellular study data suggest that UA and US597 modulate expression of cell adhesion molecules within focal adhesion signaling pathway leading to cancer cell motility.

No MeSH data available.


Related in: MedlinePlus