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Ethanol extract of Forsythia suspensa root induces apoptosis of esophageal carcinoma cells via the mitochondrial apoptotic pathway.

Zhao L, Yan X, Shi J, Ren F, Liu L, Sun S, Shan B - Mol Med Rep (2014)

Bottom Line: The results revealed that FSREE, rather than Forsythia suspensa ethanolic extracts from the leaf (FSLEE) and fruit (FSFEE) exhibited marked anti-tumor activity towards human esophageal cancer cells.FSREE induced cancer cell apoptosis and growth arrest by downregulating B‑cell lymphoma (Bcl)‑2, Bcl‑extra large and myeloid cell leukemia 1, while upregulating Bcl‑2‑associated X protein, Bcl‑2 antagonist of cell death and phorbol‑12‑myristate‑13‑acetate‑induced protein 1.Furthermore, the anti-cancer activity of FSREE was associated with a decreased level of phosphorylated Janus kinase/signal transducer and activator of transcription 3 and extracellular‑signal‑regulated kinase signaling activity.

View Article: PubMed Central - PubMed

Affiliation: Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.

ABSTRACT
Forsythia suspensa root is used in the treatment of fever and jaundice in Traditional Chinese Medicine. In the present study, the anti-tumor activity of the ethanolic extract of Forsythia suspensa root (FSREE) against esophageal carcinoma cells was investigated in vitro and in vivo and its anti-cancer mechanism was examined. The results revealed that FSREE, rather than Forsythia suspensa ethanolic extracts from the leaf (FSLEE) and fruit (FSFEE) exhibited marked anti-tumor activity towards human esophageal cancer cells. FSREE induced cancer cell apoptosis and growth arrest by downregulating B‑cell lymphoma (Bcl)‑2, Bcl‑extra large and myeloid cell leukemia 1, while upregulating Bcl‑2‑associated X protein, Bcl‑2 antagonist of cell death and phorbol‑12‑myristate‑13‑acetate‑induced protein 1. This led to the activation of poly(ADP ribose) polymerase, caspase‑3 and caspase‑9, but not caspase‑8. Furthermore, the anti-cancer activity of FSREE was associated with a decreased level of phosphorylated Janus kinase/signal transducer and activator of transcription 3 and extracellular‑signal‑regulated kinase signaling activity. It was also observed that the levels of cytochrome c were elevated in the cytoplasm, accounting for the loss of mitochondrial membrane potential in the TE‑13 cells upon treatment with FSEER. In addition, FSEER inhibited the growth of esophageal cancer cells in xenograft models and no detectable toxicity was present in the lung or liver tissues. These observations provided further evidence of the anti-tumor effect of FSEER and may be of importance to further examine the potential role of Forsythia suspensa root as a therapeutic agent in esophageal carcinoma therapy.

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Reverse transcription quantitative polymerase chain reaction and western blot analysis of the protein expression of the Bcl2 family. TE-13 cells were treated with FSEER (0.25, 0.5 and 1.0 mg/ml) for 48 h and the (A) mRNA and (B) protein expression levels of Bcl-2, Bcl-xL, Mcl-1, Bax, Bad and Noxa were examined. FSEER, Forsythia suspensa ethanolic extract of the root; Bcl-2, B-cell lymphoma 2; Bcl-Xl, Bcl-extra large; Mcl-1, myeloid cell leukemia 1; Bax, Bcl-2-associated X protein; Bad; Bcl-2-associated death promoter; Noxa, phorbol-12-myristate-13-acetate-induced protein 1.
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f4-mmr-11-02-0871: Reverse transcription quantitative polymerase chain reaction and western blot analysis of the protein expression of the Bcl2 family. TE-13 cells were treated with FSEER (0.25, 0.5 and 1.0 mg/ml) for 48 h and the (A) mRNA and (B) protein expression levels of Bcl-2, Bcl-xL, Mcl-1, Bax, Bad and Noxa were examined. FSEER, Forsythia suspensa ethanolic extract of the root; Bcl-2, B-cell lymphoma 2; Bcl-Xl, Bcl-extra large; Mcl-1, myeloid cell leukemia 1; Bax, Bcl-2-associated X protein; Bad; Bcl-2-associated death promoter; Noxa, phorbol-12-myristate-13-acetate-induced protein 1.

Mentions: Mitochondrial integrity is regulated by the Bcl-2 family, which is constituted of pro-apoptotic members, including Bcl-2, Bcl-xL and myeloid cell leukemia 1 (Mcl-1), and anti-apoptotic members, including Bax, Bcl-2-associated death promoter (Bad) and phorbol-12-myristate-13-acetate-induced protein 1 (Noxa) (17,18). Thus, the expression of these Bcl-2 family members was detected in TE-13 cells following treatment with various concentrations of FSREE for different periods of time. As shown in Fig. 4A and B, a decrease in the expression of Bcl-2, Bcl-xL and Mcl-1 was observed, accompanied by an increase in the expression of Bax, Bad and Noxa mRNA in the TE-13 cells following treatment with FSEER (0.25–1 mg/ml) for 24 h (Fig. 4A). In addition, the change in the expression levels of the above proteins was consistent with the mRNA expression in response to treatment with FSEER (0.25–1 mg/ml) for 48 h (Fig. 4B). These results further demonstrated that the mitochondrial apoptotic pathway was activated by the Bcl-2 family in FSERR-induced apoptosis in esophageal cancer TE-13 cells.


Ethanol extract of Forsythia suspensa root induces apoptosis of esophageal carcinoma cells via the mitochondrial apoptotic pathway.

Zhao L, Yan X, Shi J, Ren F, Liu L, Sun S, Shan B - Mol Med Rep (2014)

Reverse transcription quantitative polymerase chain reaction and western blot analysis of the protein expression of the Bcl2 family. TE-13 cells were treated with FSEER (0.25, 0.5 and 1.0 mg/ml) for 48 h and the (A) mRNA and (B) protein expression levels of Bcl-2, Bcl-xL, Mcl-1, Bax, Bad and Noxa were examined. FSEER, Forsythia suspensa ethanolic extract of the root; Bcl-2, B-cell lymphoma 2; Bcl-Xl, Bcl-extra large; Mcl-1, myeloid cell leukemia 1; Bax, Bcl-2-associated X protein; Bad; Bcl-2-associated death promoter; Noxa, phorbol-12-myristate-13-acetate-induced protein 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4262507&req=5

f4-mmr-11-02-0871: Reverse transcription quantitative polymerase chain reaction and western blot analysis of the protein expression of the Bcl2 family. TE-13 cells were treated with FSEER (0.25, 0.5 and 1.0 mg/ml) for 48 h and the (A) mRNA and (B) protein expression levels of Bcl-2, Bcl-xL, Mcl-1, Bax, Bad and Noxa were examined. FSEER, Forsythia suspensa ethanolic extract of the root; Bcl-2, B-cell lymphoma 2; Bcl-Xl, Bcl-extra large; Mcl-1, myeloid cell leukemia 1; Bax, Bcl-2-associated X protein; Bad; Bcl-2-associated death promoter; Noxa, phorbol-12-myristate-13-acetate-induced protein 1.
Mentions: Mitochondrial integrity is regulated by the Bcl-2 family, which is constituted of pro-apoptotic members, including Bcl-2, Bcl-xL and myeloid cell leukemia 1 (Mcl-1), and anti-apoptotic members, including Bax, Bcl-2-associated death promoter (Bad) and phorbol-12-myristate-13-acetate-induced protein 1 (Noxa) (17,18). Thus, the expression of these Bcl-2 family members was detected in TE-13 cells following treatment with various concentrations of FSREE for different periods of time. As shown in Fig. 4A and B, a decrease in the expression of Bcl-2, Bcl-xL and Mcl-1 was observed, accompanied by an increase in the expression of Bax, Bad and Noxa mRNA in the TE-13 cells following treatment with FSEER (0.25–1 mg/ml) for 24 h (Fig. 4A). In addition, the change in the expression levels of the above proteins was consistent with the mRNA expression in response to treatment with FSEER (0.25–1 mg/ml) for 48 h (Fig. 4B). These results further demonstrated that the mitochondrial apoptotic pathway was activated by the Bcl-2 family in FSERR-induced apoptosis in esophageal cancer TE-13 cells.

Bottom Line: The results revealed that FSREE, rather than Forsythia suspensa ethanolic extracts from the leaf (FSLEE) and fruit (FSFEE) exhibited marked anti-tumor activity towards human esophageal cancer cells.FSREE induced cancer cell apoptosis and growth arrest by downregulating B‑cell lymphoma (Bcl)‑2, Bcl‑extra large and myeloid cell leukemia 1, while upregulating Bcl‑2‑associated X protein, Bcl‑2 antagonist of cell death and phorbol‑12‑myristate‑13‑acetate‑induced protein 1.Furthermore, the anti-cancer activity of FSREE was associated with a decreased level of phosphorylated Janus kinase/signal transducer and activator of transcription 3 and extracellular‑signal‑regulated kinase signaling activity.

View Article: PubMed Central - PubMed

Affiliation: Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.

ABSTRACT
Forsythia suspensa root is used in the treatment of fever and jaundice in Traditional Chinese Medicine. In the present study, the anti-tumor activity of the ethanolic extract of Forsythia suspensa root (FSREE) against esophageal carcinoma cells was investigated in vitro and in vivo and its anti-cancer mechanism was examined. The results revealed that FSREE, rather than Forsythia suspensa ethanolic extracts from the leaf (FSLEE) and fruit (FSFEE) exhibited marked anti-tumor activity towards human esophageal cancer cells. FSREE induced cancer cell apoptosis and growth arrest by downregulating B‑cell lymphoma (Bcl)‑2, Bcl‑extra large and myeloid cell leukemia 1, while upregulating Bcl‑2‑associated X protein, Bcl‑2 antagonist of cell death and phorbol‑12‑myristate‑13‑acetate‑induced protein 1. This led to the activation of poly(ADP ribose) polymerase, caspase‑3 and caspase‑9, but not caspase‑8. Furthermore, the anti-cancer activity of FSREE was associated with a decreased level of phosphorylated Janus kinase/signal transducer and activator of transcription 3 and extracellular‑signal‑regulated kinase signaling activity. It was also observed that the levels of cytochrome c were elevated in the cytoplasm, accounting for the loss of mitochondrial membrane potential in the TE‑13 cells upon treatment with FSEER. In addition, FSEER inhibited the growth of esophageal cancer cells in xenograft models and no detectable toxicity was present in the lung or liver tissues. These observations provided further evidence of the anti-tumor effect of FSEER and may be of importance to further examine the potential role of Forsythia suspensa root as a therapeutic agent in esophageal carcinoma therapy.

Show MeSH
Related in: MedlinePlus