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Berberine, a natural compound, suppresses Hedgehog signaling pathway activity and cancer growth.

Wang J, Peng Y, Liu Y, Yang J, Ding N, Tan W - BMC Cancer (2015)

Bottom Line: Many studies have revealed that BBR possesses anticancer effect.In this study, we found that BBR significantly inhibited the Hh pathway activity.Meanwhile, we observed that BBR failed to affect the transcriptional factors activities provoked by tumor necrosis factor-α (TNF-α) and Prostaglandin E2 (PGE2), thus suggesting its unique property against Hh pathway activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P.R. China. 13211030033@fudan.edu.cn.

ABSTRACT

Background: Berberine (BBR), a natural alkaloid compound, is used as a non-prescription drug in China for treating diarrhea and gastroenteritis. Many studies have revealed that BBR possesses anticancer effect. However, the molecular mechanisms underlying its anticancer action is far from being fully elucidated. This study is aimed to determine the effect of BBR on the hedgehog (Hh) activity and the growth of cancers addiction to Hh activity.

Methods: The Hh activity was determined by dual luciferase assays and quantitative RT-PCR analyses. The growth inhibition of BBR on medulloblastoma which was obtained from ptch+/-;p53-/- mice was analyzed by 5-bromo-2-deoxyuridine (Brdu) assays and by allografting the medulloblastoma into nude mice. The data were statistically analyzed by one-way analysis of variance (ANOVA), and multiple comparison between the groups was performed using Dunnett's method.

Results: In this study, we found that BBR significantly inhibited the Hh pathway activity. Meanwhile, we observed that BBR failed to affect the transcriptional factors activities provoked by tumor necrosis factor-α (TNF-α) and Prostaglandin E2 (PGE2), thus suggesting its unique property against Hh pathway activity. Further studies revealed that BBR inhibited the Hh pathway activity by potentially targeting the critical component Smoothened (Smo) and most likely shared the same binding site on Smo with cyclopamine, a classical Smo inhibitor. Finally, we demonstrated that BBR obviously suppressed the Hh-dependent medulloblastoma growth in vitro and in vivo.

Conclusion: Collectively, our study uncovered a novel molecular mechanism responsible for the anticancer action of BBR, thus opening the way for the usage of BBR for therapeutics of cancers addiction to aberrant Hh pathway activity.

No MeSH data available.


Related in: MedlinePlus

BBR inhibits the growth of medullboblastoma in vivo. a Inhibitory effect of BBR on the growth of medulloblastoma in vivo. Nude mice allografted with medulloblastoma were administered the BBR 100 mg/kg by daily gavage for 21 days. RTV for indicated days was shown as mean ± s.d. for each group of mice. (b-c) BBR inhibited the Gli1 mRNA (b) and ptch1 mRNA (c) expression in the medulloblastoma tissues isolated from nude mice. Four hours after last dose of BBR administration, the medulloblastom tissues were harvested for RT-qPCR analysis. Data are expressed as mean ± s.d. *p < 0.05
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Fig5: BBR inhibits the growth of medullboblastoma in vivo. a Inhibitory effect of BBR on the growth of medulloblastoma in vivo. Nude mice allografted with medulloblastoma were administered the BBR 100 mg/kg by daily gavage for 21 days. RTV for indicated days was shown as mean ± s.d. for each group of mice. (b-c) BBR inhibited the Gli1 mRNA (b) and ptch1 mRNA (c) expression in the medulloblastoma tissues isolated from nude mice. Four hours after last dose of BBR administration, the medulloblastom tissues were harvested for RT-qPCR analysis. Data are expressed as mean ± s.d. *p < 0.05

Mentions: To further demonstrate that BBR may inhibit the growth of the Hh-dependent medulloblastoma growth, we allografted the medulloblastoma isolated from ptch+/−;p53−/− mice into the Nude mice. BBR was administrated by gavage by 100 mg/kg daily. Consistent with the in vitro data, BBR significantly inhibited the medulloblastoma growth (Fig. 5a), which is accompanied with similar reduction of the mRNA expression of Gli1 (Fig. 5b), and ptch1 (Fig. 5c). Hence, our in vivo data further demonstrate that BBR may inhibit the growth of Hh-dependent medulloblastoma growth by inhibiting the Hh pathway activity.Fig. 5


Berberine, a natural compound, suppresses Hedgehog signaling pathway activity and cancer growth.

Wang J, Peng Y, Liu Y, Yang J, Ding N, Tan W - BMC Cancer (2015)

BBR inhibits the growth of medullboblastoma in vivo. a Inhibitory effect of BBR on the growth of medulloblastoma in vivo. Nude mice allografted with medulloblastoma were administered the BBR 100 mg/kg by daily gavage for 21 days. RTV for indicated days was shown as mean ± s.d. for each group of mice. (b-c) BBR inhibited the Gli1 mRNA (b) and ptch1 mRNA (c) expression in the medulloblastoma tissues isolated from nude mice. Four hours after last dose of BBR administration, the medulloblastom tissues were harvested for RT-qPCR analysis. Data are expressed as mean ± s.d. *p < 0.05
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4546096&req=5

Fig5: BBR inhibits the growth of medullboblastoma in vivo. a Inhibitory effect of BBR on the growth of medulloblastoma in vivo. Nude mice allografted with medulloblastoma were administered the BBR 100 mg/kg by daily gavage for 21 days. RTV for indicated days was shown as mean ± s.d. for each group of mice. (b-c) BBR inhibited the Gli1 mRNA (b) and ptch1 mRNA (c) expression in the medulloblastoma tissues isolated from nude mice. Four hours after last dose of BBR administration, the medulloblastom tissues were harvested for RT-qPCR analysis. Data are expressed as mean ± s.d. *p < 0.05
Mentions: To further demonstrate that BBR may inhibit the growth of the Hh-dependent medulloblastoma growth, we allografted the medulloblastoma isolated from ptch+/−;p53−/− mice into the Nude mice. BBR was administrated by gavage by 100 mg/kg daily. Consistent with the in vitro data, BBR significantly inhibited the medulloblastoma growth (Fig. 5a), which is accompanied with similar reduction of the mRNA expression of Gli1 (Fig. 5b), and ptch1 (Fig. 5c). Hence, our in vivo data further demonstrate that BBR may inhibit the growth of Hh-dependent medulloblastoma growth by inhibiting the Hh pathway activity.Fig. 5

Bottom Line: Many studies have revealed that BBR possesses anticancer effect.In this study, we found that BBR significantly inhibited the Hh pathway activity.Meanwhile, we observed that BBR failed to affect the transcriptional factors activities provoked by tumor necrosis factor-α (TNF-α) and Prostaglandin E2 (PGE2), thus suggesting its unique property against Hh pathway activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P.R. China. 13211030033@fudan.edu.cn.

ABSTRACT

Background: Berberine (BBR), a natural alkaloid compound, is used as a non-prescription drug in China for treating diarrhea and gastroenteritis. Many studies have revealed that BBR possesses anticancer effect. However, the molecular mechanisms underlying its anticancer action is far from being fully elucidated. This study is aimed to determine the effect of BBR on the hedgehog (Hh) activity and the growth of cancers addiction to Hh activity.

Methods: The Hh activity was determined by dual luciferase assays and quantitative RT-PCR analyses. The growth inhibition of BBR on medulloblastoma which was obtained from ptch+/-;p53-/- mice was analyzed by 5-bromo-2-deoxyuridine (Brdu) assays and by allografting the medulloblastoma into nude mice. The data were statistically analyzed by one-way analysis of variance (ANOVA), and multiple comparison between the groups was performed using Dunnett's method.

Results: In this study, we found that BBR significantly inhibited the Hh pathway activity. Meanwhile, we observed that BBR failed to affect the transcriptional factors activities provoked by tumor necrosis factor-α (TNF-α) and Prostaglandin E2 (PGE2), thus suggesting its unique property against Hh pathway activity. Further studies revealed that BBR inhibited the Hh pathway activity by potentially targeting the critical component Smoothened (Smo) and most likely shared the same binding site on Smo with cyclopamine, a classical Smo inhibitor. Finally, we demonstrated that BBR obviously suppressed the Hh-dependent medulloblastoma growth in vitro and in vivo.

Conclusion: Collectively, our study uncovered a novel molecular mechanism responsible for the anticancer action of BBR, thus opening the way for the usage of BBR for therapeutics of cancers addiction to aberrant Hh pathway activity.

No MeSH data available.


Related in: MedlinePlus