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Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets.

ABSTRACT: Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), found in cooked meat, is a known food carcinogen that causes several types of cancer, including breast cancer, as PhIP metabolites produce DNA adduct and DNA strand breaks. Curcumin, obtained from the rhizome of Curcuma longa, has potent anticancer activity. To date, no study has examined the interaction of PhIP with curcumin in breast epithelial cells. The present study demonstrates the mechanisms by which curcumin inhibits PhIP-induced cytotoxicity in normal breast epithelial cells (MCF-10A). Curcumin significantly inhibited PhIP-induced DNA adduct formation and DNA double stand breaks with a concomitant decrease in reactive oxygen species (ROS) production. The expression of Nrf2, FOXO targets; DNA repair genes BRCA-1, H2AFX and PARP-1; and tumor suppressor P16 was studied to evaluate the influence on these core signaling pathways. PhIP induced the expression of various antioxidant and DNA repair genes. However, co-treatment with curcumin inhibited this expression. PhIP suppressed the expression of the tumor suppressor P16 gene, whereas curcumin co-treatment increased its expression. Caspase-3 and -9 were slightly suppressed by curcumin with a consequent inhibition of cell death. These results suggest that curcumin appears to be an effective anti-PhIP food additive likely acting through multiple molecular targets.

SUBMITTER: Jain A

PROVIDER: S-EPMC7742852 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets.

Jain Ashok A Samykutty Abhilash A Jackson Carissa C Browning Darren D Bollag Wendy B WB Thangaraju Muthusamy M Takahashi Satoru S Singh Shree Ram SR

Cancer letters 20150521 1

Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), found in cooked meat, is a known food carcinogen that causes several types of cancer, including breast cancer, as PhIP metabolites produce DNA adduct and DNA strand breaks. Curcumin, obtained from the rhizome of Curcuma longa, has potent anticancer activity. To date, no study has examined the interaction of PhIP with curcumin in breast epithelial cells. The present study demonstrates the mechanisms by which curcumin inhibits PhIP-induced cyto ...[more]

PMID: 26004342

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Project description:Background: Curcumin (CUR) displays the capability of suppressing the proliferation and metastasis of various cancer cells. However, the effects and underline mechanisms of CUR to treat triple-negative breast cancer (TNBC) have not been systematically elucidated with an appropriate method. Methods: In the present research, a combination method of network pharmacology, molecular docking, and in vitro bio-experiment was used to investigate the pharmacological actions and underline mechanisms of CUR against TNBC. First, common targets of CUR and TNBC were screened via Venny 2.1.0 after potential CUR-related targets and targets of TNBC were got from several public databases. Then, the Gene Ontology (GO) function and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed on the Metascape website, and the network of compound-targets-pathways was constructed via Cytoscape software. Moreover, the network of protein-protein interaction was constructed by the STRING database to screen potential targets. Moreover, molecular docking was applied to affirm the interaction of CUR with the screened top 10 potential targets. Finally, in vitro experiments were used to further verify the effects and mechanisms of CUR and its nano-formulation (CUR-NPs) against TNBC. Results: Forty potential targets of CUR against TNBC were obtained. STAT3, AKT1, TNF, PTGS2, MMP9, EGFR, PPARG, NFE2L2, EP300, and GSK3B were identified as the top 10 targets of CUR against TNBC. In vitro experiment verified that CUR and CUR-NPs could not only restrain the invasion, migration, and proliferation of MDA-MB-231 cells but also induce their apoptosis. In addition, molecular docking demonstrated that CUR could bind spontaneously with the screened top 10 targeted proteins, and a real-time PCR experiment demonstrated that both CUR and CUR-NPs could downregulate the genetic expression levels of the 10 targets. Moreover, according to the CUR-targets-pathways network, PI3K-Akt, EGFR tyrosine kinase inhibitor resistance, JAK-STAT, Foxo, and HIF-1 signaling pathways were identified as the important pathways of CUR effects on TNBC. Among them, the inhibiting effects of CUR and CUR-NPs on the JAK-STAT signaling pathway were further verified by the western blot analysis. Conclusion: Taken together, the present research demonstrates that CUR and CUR-NPs have pharmacological effects against TNBC via a multi-target and multi-pathway manner.

Project description:BackgroundBreast cancer cell lines are frequently used as model systems to study the cellular properties and biology of breast cancer. Our objective was to characterize a large, commonly employed panel of breast cancer cell lines obtained from the American Type Culture Collection (ATCC 30-4500 K) to enable researchers to make more informed decisions in selecting cell lines for specific studies. Information about these cell lines was obtained from a wide variety of sources. In addition, new information about cellular pathways that are activated within each cell line was generated.MethodsWe determined key protein expression data using immunoblot analyses. In addition, two analyses on serum-starved cells were carried out to identify cellular proteins and pathways that are activated in these cells. These analyses were performed using a commercial PathScan array and a novel and more extensive phosphopeptide-based kinome analysis that queries 1290 phosphorylation events in major signaling pathways. Data about this panel of breast cancer cell lines was also accessed from several online sources, compiled and summarized for the following areas: molecular classification, mRNA expression, mutational status of key proteins and other possible cancer-associated mutations, and the tumorigenic and metastatic capacity in mouse xenograft models of breast cancer.ResultsThe cell lines that were characterized included 10 estrogen receptor (ER)-positive, 12 human epidermal growth factor receptor 2 (HER2)-amplified and 18 triple negative breast cancer cell lines, in addition to 4 non-tumorigenic breast cell lines. Within each subtype, there was significant genetic heterogeneity that could impact both the selection of model cell lines and the interpretation of the results obtained. To capture the net activation of key signaling pathways as a result of these mutational combinations, profiled pathway activation status was examined. This provided further clarity for which cell lines were particularly deregulated in common or unique ways.ConclusionsThese two new kinase or "Kin-OMIC" analyses add another dimension of important data about these frequently used breast cancer cell lines. This will assist researchers in selecting the most appropriate cell lines to use for breast cancer studies and provide context for the interpretation of the emerging results.

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Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets.

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Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets.

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