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Methyl Sartortuoate Inhibits Colon Cancer Cell Growth by Inducing Apoptosis and G2/M-Phase Arrest.

Lan Q, Li S, Lai W, Xu H, Zhang Y, Zeng Y, Lan W, Chu Z - Int J Mol Sci (2015)

Bottom Line: Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53, suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways.This resulted in cell cycle arrest at the G2-M phase and apoptosis in LoVo and RKO cells.Taken together, these findings suggest that methyl sartortuoate is capable of leading to activation of caspase-8, -9, -3, increasing p53 and Bax/Bcl-2 ratio apoptosis through MAPK-dependent apoptosis and results in G2-M phase arrest in LoVo and RKO cells.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. lansysu@foxmail.com.

ABSTRACT
The potential anti-neoplastic activity of terpenoids is of continued interest. In this study, we investigate whether methyl sartortuoate, a terpenoid isolated from soft coral, induced cell cycle arrest and apoptosis in a human colon cancer cell line. Culture studies found that methyl sartortuoate inhibited colon cancer cell (LoVo and RKO) growth and caused apoptotic death in a concentration- and time-dependent manner, by activation of caspase-8, caspase-9, caspase-3, p53 and Bax, and inactivation of B-cell lymphoma 2 (Bcl-2) apoptosis regulating proteins. Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53, suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways. Methyl sartortuoate also up-regulated phospho-JNK and phospho-p38 expression levels. This resulted in cell cycle arrest at the G2-M phase and apoptosis in LoVo and RKO cells. Treatment with the JNK inhibitor SP600125 and the p38 MAPK inhibitor SB203580 prevented methyl sartortuoate-induced apoptosis in LoVo cells. Moreover, methyl sartortuoate also prevented neoplasm growth in NOD-SCID nude mice inoculated with LoVo cells. Taken together, these findings suggest that methyl sartortuoate is capable of leading to activation of caspase-8, -9, -3, increasing p53 and Bax/Bcl-2 ratio apoptosis through MAPK-dependent apoptosis and results in G2-M phase arrest in LoVo and RKO cells. Thus, methyl sartortuoate may be a promising anticancer candidate.

No MeSH data available.


Related in: MedlinePlus

The apoptotic effects of Methyl Sartortuoate in LoVo and RKO cells. (A,C) Dose-and-effect results of Methyl Sartortuoate treated LoVo and RKO cells. LoVo and RKO cells were treated with Methyl Sartortuoate at the indicated concentration for 24 h. Apoptosis was examined by the annexin V flow cytometric assay method (n = 3). The percentage of apoptotic cells was scored after cell exposure to Methyl Sartortuoate. *p < 0.05, **p < 0.01, ***p < 0.001 versus control group; (B,D) Time-and-effect results of Methyl Sartortuoate-treated LoVo and RKO cells by the annexin V flow cytometric assay method (n = 3). LoVo and RKO cells were treated with Methyl Sartortuoate at 50 µM for 0, 6, 12 and 24 h. The percentage of apoptotic cells were scored after cell exposure to Methyl Sartortuoate for the indicated time at 50 µM. *p < 0.05, **p < 0.01, ***p < 0.001 versus 0 h.
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ijms-16-19401-f002: The apoptotic effects of Methyl Sartortuoate in LoVo and RKO cells. (A,C) Dose-and-effect results of Methyl Sartortuoate treated LoVo and RKO cells. LoVo and RKO cells were treated with Methyl Sartortuoate at the indicated concentration for 24 h. Apoptosis was examined by the annexin V flow cytometric assay method (n = 3). The percentage of apoptotic cells was scored after cell exposure to Methyl Sartortuoate. *p < 0.05, **p < 0.01, ***p < 0.001 versus control group; (B,D) Time-and-effect results of Methyl Sartortuoate-treated LoVo and RKO cells by the annexin V flow cytometric assay method (n = 3). LoVo and RKO cells were treated with Methyl Sartortuoate at 50 µM for 0, 6, 12 and 24 h. The percentage of apoptotic cells were scored after cell exposure to Methyl Sartortuoate for the indicated time at 50 µM. *p < 0.05, **p < 0.01, ***p < 0.001 versus 0 h.

Mentions: The effect of methyl sartortuoate on the induction of apoptosis in LoVo and RKO cells was examined using Annexin V/PI staining. Following exposure to methyl sartortuoate at concentrations of 10, 30 and 50 µM, the apoptotic population was significantly higher than control cells (p < 0.01; Figure 2A,C). When LoVo and RKO cells were treated for 6, 12 and 24 h with 50 µM methyl sartortuoate, the apoptotic cell populations also were significantly higher than control cells (p < 0.01; Figure 2B,D).


Methyl Sartortuoate Inhibits Colon Cancer Cell Growth by Inducing Apoptosis and G2/M-Phase Arrest.

Lan Q, Li S, Lai W, Xu H, Zhang Y, Zeng Y, Lan W, Chu Z - Int J Mol Sci (2015)

The apoptotic effects of Methyl Sartortuoate in LoVo and RKO cells. (A,C) Dose-and-effect results of Methyl Sartortuoate treated LoVo and RKO cells. LoVo and RKO cells were treated with Methyl Sartortuoate at the indicated concentration for 24 h. Apoptosis was examined by the annexin V flow cytometric assay method (n = 3). The percentage of apoptotic cells was scored after cell exposure to Methyl Sartortuoate. *p < 0.05, **p < 0.01, ***p < 0.001 versus control group; (B,D) Time-and-effect results of Methyl Sartortuoate-treated LoVo and RKO cells by the annexin V flow cytometric assay method (n = 3). LoVo and RKO cells were treated with Methyl Sartortuoate at 50 µM for 0, 6, 12 and 24 h. The percentage of apoptotic cells were scored after cell exposure to Methyl Sartortuoate for the indicated time at 50 µM. *p < 0.05, **p < 0.01, ***p < 0.001 versus 0 h.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581303&req=5

ijms-16-19401-f002: The apoptotic effects of Methyl Sartortuoate in LoVo and RKO cells. (A,C) Dose-and-effect results of Methyl Sartortuoate treated LoVo and RKO cells. LoVo and RKO cells were treated with Methyl Sartortuoate at the indicated concentration for 24 h. Apoptosis was examined by the annexin V flow cytometric assay method (n = 3). The percentage of apoptotic cells was scored after cell exposure to Methyl Sartortuoate. *p < 0.05, **p < 0.01, ***p < 0.001 versus control group; (B,D) Time-and-effect results of Methyl Sartortuoate-treated LoVo and RKO cells by the annexin V flow cytometric assay method (n = 3). LoVo and RKO cells were treated with Methyl Sartortuoate at 50 µM for 0, 6, 12 and 24 h. The percentage of apoptotic cells were scored after cell exposure to Methyl Sartortuoate for the indicated time at 50 µM. *p < 0.05, **p < 0.01, ***p < 0.001 versus 0 h.
Mentions: The effect of methyl sartortuoate on the induction of apoptosis in LoVo and RKO cells was examined using Annexin V/PI staining. Following exposure to methyl sartortuoate at concentrations of 10, 30 and 50 µM, the apoptotic population was significantly higher than control cells (p < 0.01; Figure 2A,C). When LoVo and RKO cells were treated for 6, 12 and 24 h with 50 µM methyl sartortuoate, the apoptotic cell populations also were significantly higher than control cells (p < 0.01; Figure 2B,D).

Bottom Line: Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53, suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways.This resulted in cell cycle arrest at the G2-M phase and apoptosis in LoVo and RKO cells.Taken together, these findings suggest that methyl sartortuoate is capable of leading to activation of caspase-8, -9, -3, increasing p53 and Bax/Bcl-2 ratio apoptosis through MAPK-dependent apoptosis and results in G2-M phase arrest in LoVo and RKO cells.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. lansysu@foxmail.com.

ABSTRACT
The potential anti-neoplastic activity of terpenoids is of continued interest. In this study, we investigate whether methyl sartortuoate, a terpenoid isolated from soft coral, induced cell cycle arrest and apoptosis in a human colon cancer cell line. Culture studies found that methyl sartortuoate inhibited colon cancer cell (LoVo and RKO) growth and caused apoptotic death in a concentration- and time-dependent manner, by activation of caspase-8, caspase-9, caspase-3, p53 and Bax, and inactivation of B-cell lymphoma 2 (Bcl-2) apoptosis regulating proteins. Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53, suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways. Methyl sartortuoate also up-regulated phospho-JNK and phospho-p38 expression levels. This resulted in cell cycle arrest at the G2-M phase and apoptosis in LoVo and RKO cells. Treatment with the JNK inhibitor SP600125 and the p38 MAPK inhibitor SB203580 prevented methyl sartortuoate-induced apoptosis in LoVo cells. Moreover, methyl sartortuoate also prevented neoplasm growth in NOD-SCID nude mice inoculated with LoVo cells. Taken together, these findings suggest that methyl sartortuoate is capable of leading to activation of caspase-8, -9, -3, increasing p53 and Bax/Bcl-2 ratio apoptosis through MAPK-dependent apoptosis and results in G2-M phase arrest in LoVo and RKO cells. Thus, methyl sartortuoate may be a promising anticancer candidate.

No MeSH data available.


Related in: MedlinePlus