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Ophiobolin O isolated from Aspergillus ustus induces G1 arrest of MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling.

Lv C, Qin W, Zhu T, Wei S, Hong K, Zhu W, Chen R, Huang C - Mar Drugs (2015)

Bottom Line: However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear.In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models.Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. lvcuiting961021@126.com.

ABSTRACT
Ophiobolin O is a member of ophiobolin family, which has been proved to be a potent anti-tumor drug candidate for human breast cancer. However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear. In this study, we further verified ophiobolin O-induced G1 phase arrest in human breast cancer MCF-7 cells, and found that ophiobolin O reduced the phosphorylation level of AKT and GSK3β, and induced down-regulation of cyclin D1. The inverse docking (INVDOCK) analysis indicated that ophiobolin O could bind to GSK3β, and GSK3β knockdown abolished cyclin D1 degradation and G1 phase arrest. Pre-treatment with phosphatase inhibitor sodium or thovanadate halted dephosphorylation of AKT and GSK3β, and blocked ophiobolin O-induced G1 phase arrest. These data suggest that ophiobolin O may induce G1 arrest in MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling. In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models. Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.

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Effect of ophiobolin O on tumor growth. (A) BALB/c male athymic mice were injected 5 × 106 MCF-7 cells s.c. for the development of subcutaneous tumors. The mice were randomized into five groups and treated with Vehicle (1% DMSO), 10 mg/kg PTX or various concentrations of ophiobolin O (5, 10, or 20 mg/kg) i.v. every four days until sacrifice according to the protocol in panel (A); (B) Tumor image from various treatment groups; (C) Average tumor mass at sacrifice; (D) Tumor volume measurements; (E) Body weight during the treatment.
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marinedrugs-13-00431-f005: Effect of ophiobolin O on tumor growth. (A) BALB/c male athymic mice were injected 5 × 106 MCF-7 cells s.c. for the development of subcutaneous tumors. The mice were randomized into five groups and treated with Vehicle (1% DMSO), 10 mg/kg PTX or various concentrations of ophiobolin O (5, 10, or 20 mg/kg) i.v. every four days until sacrifice according to the protocol in panel (A); (B) Tumor image from various treatment groups; (C) Average tumor mass at sacrifice; (D) Tumor volume measurements; (E) Body weight during the treatment.

Mentions: To evaluate whether ophiobolin O inhibits tumor growth in vivo, MCF-7 cells were injected s.c. into the right armpit of six-week old BALB/c female athymic mice. The injected carcinoma cells grew into palpable tumors in the nude mice within 10 days (Figure 5A). Paclitaxel (PTX)-treated mice (10 mg/kg) were used as positive control to assess the effect and toxicity of ophiobolin O. In this study, the tumor growth in mice treated with ophiobolin O (5, 10, or 20 mg/kg/day) was dose-dependently slowed (Figure 5B,C). Tumor volume was significantly reduced during ophiobolin O treatment (Figure 5E). The inhibitory rates at 50th day of 5, 10, and 20 mg/kg ophiobolin O treatment group were 34.62%, 46.15%, and 69.23%, respectively. The 20 mg/kg ophiobolin O treatment showed nearly equivalent effect compared to positive control (inhibition rate of 73.08%). Furthermore, no significant weight loss was observed during the course of ophiobolin O treatment, indicating there is feasibility for upward adjustment of dosage for improved treatment outcomes (Figure 5D).


Ophiobolin O isolated from Aspergillus ustus induces G1 arrest of MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling.

Lv C, Qin W, Zhu T, Wei S, Hong K, Zhu W, Chen R, Huang C - Mar Drugs (2015)

Effect of ophiobolin O on tumor growth. (A) BALB/c male athymic mice were injected 5 × 106 MCF-7 cells s.c. for the development of subcutaneous tumors. The mice were randomized into five groups and treated with Vehicle (1% DMSO), 10 mg/kg PTX or various concentrations of ophiobolin O (5, 10, or 20 mg/kg) i.v. every four days until sacrifice according to the protocol in panel (A); (B) Tumor image from various treatment groups; (C) Average tumor mass at sacrifice; (D) Tumor volume measurements; (E) Body weight during the treatment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4306945&req=5

marinedrugs-13-00431-f005: Effect of ophiobolin O on tumor growth. (A) BALB/c male athymic mice were injected 5 × 106 MCF-7 cells s.c. for the development of subcutaneous tumors. The mice were randomized into five groups and treated with Vehicle (1% DMSO), 10 mg/kg PTX or various concentrations of ophiobolin O (5, 10, or 20 mg/kg) i.v. every four days until sacrifice according to the protocol in panel (A); (B) Tumor image from various treatment groups; (C) Average tumor mass at sacrifice; (D) Tumor volume measurements; (E) Body weight during the treatment.
Mentions: To evaluate whether ophiobolin O inhibits tumor growth in vivo, MCF-7 cells were injected s.c. into the right armpit of six-week old BALB/c female athymic mice. The injected carcinoma cells grew into palpable tumors in the nude mice within 10 days (Figure 5A). Paclitaxel (PTX)-treated mice (10 mg/kg) were used as positive control to assess the effect and toxicity of ophiobolin O. In this study, the tumor growth in mice treated with ophiobolin O (5, 10, or 20 mg/kg/day) was dose-dependently slowed (Figure 5B,C). Tumor volume was significantly reduced during ophiobolin O treatment (Figure 5E). The inhibitory rates at 50th day of 5, 10, and 20 mg/kg ophiobolin O treatment group were 34.62%, 46.15%, and 69.23%, respectively. The 20 mg/kg ophiobolin O treatment showed nearly equivalent effect compared to positive control (inhibition rate of 73.08%). Furthermore, no significant weight loss was observed during the course of ophiobolin O treatment, indicating there is feasibility for upward adjustment of dosage for improved treatment outcomes (Figure 5D).

Bottom Line: However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear.In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models.Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. lvcuiting961021@126.com.

ABSTRACT
Ophiobolin O is a member of ophiobolin family, which has been proved to be a potent anti-tumor drug candidate for human breast cancer. However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear. In this study, we further verified ophiobolin O-induced G1 phase arrest in human breast cancer MCF-7 cells, and found that ophiobolin O reduced the phosphorylation level of AKT and GSK3β, and induced down-regulation of cyclin D1. The inverse docking (INVDOCK) analysis indicated that ophiobolin O could bind to GSK3β, and GSK3β knockdown abolished cyclin D1 degradation and G1 phase arrest. Pre-treatment with phosphatase inhibitor sodium or thovanadate halted dephosphorylation of AKT and GSK3β, and blocked ophiobolin O-induced G1 phase arrest. These data suggest that ophiobolin O may induce G1 arrest in MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling. In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models. Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.

Show MeSH
Related in: MedlinePlus