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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) Expression of ICAM-1 on HUVECs determined by flow cytometry, and (B) the inhibitory effect of UA/US597 on the expression of ICAM-1, VCAM-1 and E-selectin, silver area is an isotype control, blank curve as a control, blue curve represents UA (5 μM) treated group, yellow, purple and red line represents US597 treated group at concentrations of 0.2, 1 and 5 μM, respectively(C) Quantitative real-time PCR assay of the inhibitory effect of UA/US597 on the mRNA expression of ICAM-1, VCAM-1 and E-selectin. The expression of ICAM-1 (D), E-selectin and P-selectin (E) on HUVECs were analyzed by Western blotting. Data were expressed as the percentage of control. Bars represent the mean ± SD (n = 3); *P < 0.05 and **P < 0.01.
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Figure 3: (A) Expression of ICAM-1 on HUVECs determined by flow cytometry, and (B) the inhibitory effect of UA/US597 on the expression of ICAM-1, VCAM-1 and E-selectin, silver area is an isotype control, blank curve as a control, blue curve represents UA (5 μM) treated group, yellow, purple and red line represents US597 treated group at concentrations of 0.2, 1 and 5 μM, respectively(C) Quantitative real-time PCR assay of the inhibitory effect of UA/US597 on the mRNA expression of ICAM-1, VCAM-1 and E-selectin. The expression of ICAM-1 (D), E-selectin and P-selectin (E) on HUVECs were analyzed by Western blotting. Data were expressed as the percentage of control. Bars represent the mean ± SD (n = 3); *P < 0.05 and **P < 0.01.

Mentions: To verify the accurate molecular targets that UA/US597 affects the adhesion, invasion and migration of HepG2 cells, the effects of UA/US597 on the mRNA and protein expression by HUVECs of ICAM-1, VCAM-1 and E-selectin were evaluated by qRT-PCR, flow cytometry and western blot. The HUVECs were pretreated with 1 ng/mL IL-1β for 4 h, followed by treatment of the HUVECs with UA/US597 for 24 h. Figure 3C showed that US597 dose-dependently inhibited the mRNA expression of ICAM-1 and E-selectin. In addition, the mRNA expression of VCAM-1 was significantly lower in the US597 (5 μM) treated group than that in the control group (P < 0.01). UA (5 μM) inhibited the induction of ICAM-1 and E-selectin mRNA (P < 0.05), while the level of VCAM-1 mRNA showed almost no change.


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) Expression of ICAM-1 on HUVECs determined by flow cytometry, and (B) the inhibitory effect of UA/US597 on the expression of ICAM-1, VCAM-1 and E-selectin, silver area is an isotype control, blank curve as a control, blue curve represents UA (5 μM) treated group, yellow, purple and red line represents US597 treated group at concentrations of 0.2, 1 and 5 μM, respectively(C) Quantitative real-time PCR assay of the inhibitory effect of UA/US597 on the mRNA expression of ICAM-1, VCAM-1 and E-selectin. The expression of ICAM-1 (D), E-selectin and P-selectin (E) on HUVECs were analyzed by Western blotting. Data were expressed as the percentage of control. Bars represent the mean ± SD (n = 3); *P < 0.05 and **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: (A) Expression of ICAM-1 on HUVECs determined by flow cytometry, and (B) the inhibitory effect of UA/US597 on the expression of ICAM-1, VCAM-1 and E-selectin, silver area is an isotype control, blank curve as a control, blue curve represents UA (5 μM) treated group, yellow, purple and red line represents US597 treated group at concentrations of 0.2, 1 and 5 μM, respectively(C) Quantitative real-time PCR assay of the inhibitory effect of UA/US597 on the mRNA expression of ICAM-1, VCAM-1 and E-selectin. The expression of ICAM-1 (D), E-selectin and P-selectin (E) on HUVECs were analyzed by Western blotting. Data were expressed as the percentage of control. Bars represent the mean ± SD (n = 3); *P < 0.05 and **P < 0.01.
Mentions: To verify the accurate molecular targets that UA/US597 affects the adhesion, invasion and migration of HepG2 cells, the effects of UA/US597 on the mRNA and protein expression by HUVECs of ICAM-1, VCAM-1 and E-selectin were evaluated by qRT-PCR, flow cytometry and western blot. The HUVECs were pretreated with 1 ng/mL IL-1β for 4 h, followed by treatment of the HUVECs with UA/US597 for 24 h. Figure 3C showed that US597 dose-dependently inhibited the mRNA expression of ICAM-1 and E-selectin. In addition, the mRNA expression of VCAM-1 was significantly lower in the US597 (5 μM) treated group than that in the control group (P < 0.01). UA (5 μM) inhibited the induction of ICAM-1 and E-selectin mRNA (P < 0.05), while the level of VCAM-1 mRNA showed almost no change.

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