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Gene expression profiling reveals effects of Cimicifuga racemosa (L.) NUTT. (black cohosh) on the estrogen receptor positive human breast cancer cell line MCF-7.

Gaube F, Wolfl S, Pusch L, Kroll TC, Hamburger M - BMC Pharmacol. (2007)

Bottom Line: Also several transcripts coding for oxidoreductases were induced, as for example the cytochrome P450 family members 1A1 and 1B1.In addition, some transcripts associated with antitumor but also tumor-promoting activity were regulated.The effects may be results of the activation of different pathways.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Pharmacy, Department of Pharmaceutical Biology, University of Jena, Semmelweisstr, 10, 07743 Jena, Germany. Friedemann.Gaube@uni-jena.de

ABSTRACT

Background: Extracts from the rhizome of Cimicifuga racemosa (black cohosh) are increasingly popular as herbal alternative to hormone replacement therapy (HRT) for the alleviation of postmenopausal disorders. However, the molecular mode of action and the active principles are presently not clear. Previously published data have been largely contradictory. We, therefore, investigated the effects of a lipophilic black cohosh rhizome extract and cycloartane-type triterpenoids on the estrogen receptor positive human breast cancer cell line MCF-7.

Results: Both extract and purified compounds clearly inhibited cellular proliferation. Gene expression profiling with the extract allowed us to identify 431 regulated genes with high significance. The extract induced expression pattern differed from those of 17beta-estradiol or the estrogen receptor antagonist tamoxifen. We observed a significant enrichment of genes in an anti-proliferative and apoptosis-sensitizing manner, as well as an increase of mRNAs coding for gene products involved in several stress response pathways. These functional groups were highly overrepresented among all regulated genes. Also several transcripts coding for oxidoreductases were induced, as for example the cytochrome P450 family members 1A1 and 1B1. In addition, some transcripts associated with antitumor but also tumor-promoting activity were regulated. Real-Time RT-PCR analysis of 13 selected genes was conducted after treatment with purified compounds - the cycloartane-type triterpene glycoside actein and triterpene aglycons - showing similar expression levels compared to the extract.

Conclusion: No estrogenic but antiproliferative and proapoptotic gene expression was shown for black cohosh in MCF-7 cells at the transcriptional level. The effects may be results of the activation of different pathways. The cycloartane glycosides and - for the first time - their aglycons could be identified as an active principle in black cohosh.

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Functional categories of genes regulated in MCF-7 cells after 24 h incubation with black cohosh extract. Genes were grouped in 5 large groups (Apoptosis, Proliferation, General Growth, Signaling & Transport, Metabolism), some consisting of subgroups. Genes that are not clearly associated with these groups are summarized in the category others. The category stress response contains genes also grouped into one of the 6 main classes. Each bar represents the number of genes that were up- (dark) or downregulated (white) in the respective group.
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Figure 3: Functional categories of genes regulated in MCF-7 cells after 24 h incubation with black cohosh extract. Genes were grouped in 5 large groups (Apoptosis, Proliferation, General Growth, Signaling & Transport, Metabolism), some consisting of subgroups. Genes that are not clearly associated with these groups are summarized in the category others. The category stress response contains genes also grouped into one of the 6 main classes. Each bar represents the number of genes that were up- (dark) or downregulated (white) in the respective group.

Mentions: Of the genes regulated by the extract, 335 transcripts (78%) were upregulated and 96 genes (22%) were downregulated. These genes were grouped into functional categories according to Gene Ontology terms and gene description at the NetAffx™ Analysis Center [36] and addition literature search. Most of the regulated genes could be clearly assigned to 5 larger groups of functionally related genes (subgroups in brackets): apoptosis, proliferation (cell cycle, replication), general growth (RNA processing, protein turnover, transcription, cell structure and organization), signaling & transport (signal transduction, transport) and metabolism (oxidoreductases, biosynthesis and catabolism). Genes that could not be assigned to any of these groups were summarized as others (Figure 3). Furthermore, because of a striking presence of many transcripts linked to cellular stress response, we also created the functional category stress response, which is not directly linked to the other categories. Genes functionally connected to this group are already members of one of the 6 main categories (Figure 3). In most groups more genes were stimulated than inhibited. In the group proliferation, in contrast, a majority of genes appeared to be downregulated. Genes for this category as well as the groups/subgroups apoptosis, protein turnover, oxidoreductases and stress response are all statistically overrepresented among the black cohosh regulated genes (p < 0.001, two-sided p-value Fisher Exact Test). For two groups – proliferation (cell cycle, DNA replication) and stress response – the overrepresentation is very highly significant.


Gene expression profiling reveals effects of Cimicifuga racemosa (L.) NUTT. (black cohosh) on the estrogen receptor positive human breast cancer cell line MCF-7.

Gaube F, Wolfl S, Pusch L, Kroll TC, Hamburger M - BMC Pharmacol. (2007)

Functional categories of genes regulated in MCF-7 cells after 24 h incubation with black cohosh extract. Genes were grouped in 5 large groups (Apoptosis, Proliferation, General Growth, Signaling & Transport, Metabolism), some consisting of subgroups. Genes that are not clearly associated with these groups are summarized in the category others. The category stress response contains genes also grouped into one of the 6 main classes. Each bar represents the number of genes that were up- (dark) or downregulated (white) in the respective group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2194763&req=5

Figure 3: Functional categories of genes regulated in MCF-7 cells after 24 h incubation with black cohosh extract. Genes were grouped in 5 large groups (Apoptosis, Proliferation, General Growth, Signaling & Transport, Metabolism), some consisting of subgroups. Genes that are not clearly associated with these groups are summarized in the category others. The category stress response contains genes also grouped into one of the 6 main classes. Each bar represents the number of genes that were up- (dark) or downregulated (white) in the respective group.
Mentions: Of the genes regulated by the extract, 335 transcripts (78%) were upregulated and 96 genes (22%) were downregulated. These genes were grouped into functional categories according to Gene Ontology terms and gene description at the NetAffx™ Analysis Center [36] and addition literature search. Most of the regulated genes could be clearly assigned to 5 larger groups of functionally related genes (subgroups in brackets): apoptosis, proliferation (cell cycle, replication), general growth (RNA processing, protein turnover, transcription, cell structure and organization), signaling & transport (signal transduction, transport) and metabolism (oxidoreductases, biosynthesis and catabolism). Genes that could not be assigned to any of these groups were summarized as others (Figure 3). Furthermore, because of a striking presence of many transcripts linked to cellular stress response, we also created the functional category stress response, which is not directly linked to the other categories. Genes functionally connected to this group are already members of one of the 6 main categories (Figure 3). In most groups more genes were stimulated than inhibited. In the group proliferation, in contrast, a majority of genes appeared to be downregulated. Genes for this category as well as the groups/subgroups apoptosis, protein turnover, oxidoreductases and stress response are all statistically overrepresented among the black cohosh regulated genes (p < 0.001, two-sided p-value Fisher Exact Test). For two groups – proliferation (cell cycle, DNA replication) and stress response – the overrepresentation is very highly significant.

Bottom Line: Also several transcripts coding for oxidoreductases were induced, as for example the cytochrome P450 family members 1A1 and 1B1.In addition, some transcripts associated with antitumor but also tumor-promoting activity were regulated.The effects may be results of the activation of different pathways.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Pharmacy, Department of Pharmaceutical Biology, University of Jena, Semmelweisstr, 10, 07743 Jena, Germany. Friedemann.Gaube@uni-jena.de

ABSTRACT

Background: Extracts from the rhizome of Cimicifuga racemosa (black cohosh) are increasingly popular as herbal alternative to hormone replacement therapy (HRT) for the alleviation of postmenopausal disorders. However, the molecular mode of action and the active principles are presently not clear. Previously published data have been largely contradictory. We, therefore, investigated the effects of a lipophilic black cohosh rhizome extract and cycloartane-type triterpenoids on the estrogen receptor positive human breast cancer cell line MCF-7.

Results: Both extract and purified compounds clearly inhibited cellular proliferation. Gene expression profiling with the extract allowed us to identify 431 regulated genes with high significance. The extract induced expression pattern differed from those of 17beta-estradiol or the estrogen receptor antagonist tamoxifen. We observed a significant enrichment of genes in an anti-proliferative and apoptosis-sensitizing manner, as well as an increase of mRNAs coding for gene products involved in several stress response pathways. These functional groups were highly overrepresented among all regulated genes. Also several transcripts coding for oxidoreductases were induced, as for example the cytochrome P450 family members 1A1 and 1B1. In addition, some transcripts associated with antitumor but also tumor-promoting activity were regulated. Real-Time RT-PCR analysis of 13 selected genes was conducted after treatment with purified compounds - the cycloartane-type triterpene glycoside actein and triterpene aglycons - showing similar expression levels compared to the extract.

Conclusion: No estrogenic but antiproliferative and proapoptotic gene expression was shown for black cohosh in MCF-7 cells at the transcriptional level. The effects may be results of the activation of different pathways. The cycloartane glycosides and - for the first time - their aglycons could be identified as an active principle in black cohosh.

Show MeSH
Related in: MedlinePlus