curcumin and Esophageal-Squamous-Cell-Carcinoma

Curcumin shows an anti-cancer role in many kinds of tumors. However, the mechanism of its anti-tumor function in esophageal squamous cell carcinoma (ESCC) remains largely unknown. Herein, we explored the therapeutic potential of curcumin for esophageal cancer. Curcumin could time- and dose-dependently inhibit ESCC cells activity. Additionally, ESCC cells exposed to 20 μM of curcumin exhibited significantly decreased proliferative and invasive capacities, as well as enhanced cell apoptosis. ESCC tissues and cells exhibited significantly increased circNRIP1 expression when compared to their counterparts. circNRIP1 knockdown markedly impaired cell proliferation, clone formation, cell migration and invasion but promoted apoptosis. Exposure to 10-20 μM of curcumin inhibited circNRIP1 expression, however, overexpression of circNRIP1 could significantly restored the biological characteristics that were inhibited by curcumin exposure in vivo and in vitro. circNRIP1 promoted the malignancy of ESCC by combining miR-532-3p, and downstream AKT3. Curcumin inhibited AKT phosphorylation by up-regulating miR-532-3p expression, thereby inhibiting the activation of the AKT pathway. In summary, curcumin is a potent inhibitor of ESCC growth, which can be achieved through the regulation of the circNRIP1/miR-532-3p/AKT pathway. This research may provide new mechanisms for curcumin to inhibit the malignant development of ESCC.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Proto-Oncogene Proteins c-akt

Esophageal cancer responds poorly to traditional therapies, and novel treatments are needed. The phytochemical curcumin is a potential treatment for Esophageal Squamous Cell Carcinoma (ESCC). A curcumin metabolite, tetrahydrocurcumin (THCUR), has anti-cancer effects and greater bioavailability than curcumin.. Evaluate THCUR as an anti-cancer agent relative to curcumin and a standard cancer drug, 5-fluorouracil (5-FU), along with treatment interactions.. Assay cell proliferation and viability following individual and combined delivery of the compounds to three ESSC cell lines (TE-1, TE-8, and KY-5) that have different percentages of Cancer Stem Cells (CSCs).. Curcumin was significantly more effective than 5-FU in all three cell lines. It also had the greatest effect on KY-5 cells, which have the highest CSC properties, consistent with the ability of curcumin to target CSCs. Effects on ESCC cell proliferation were not detected from 40µM THCUR, a dosage above the IC50 of curcumin and 5-FU. However, THCUR at this dosage in combination with 5-FU significantly suppressed TE-1 cell proliferation, but 5-FU alone did not. As TE-1 has low CSC properties relative to the two other cell lines, it was expected to have the least resistance to chemotherapeutic treatments. Surprisingly, TE-1 was the most resistant to inhibition by 5-FU.. These results and the greater stability and water solubility of THCUR than curcumin support further testing of THCUR in combination with standard treatments, particularly for chemoresistant ESCC. In contrast to concerns that curcuminoids taken by patients through diet or diet supplements might interfere with chemotherapy, suppression of 5-FU efficacy by curcumin was not observed.

Topics: Antineoplastic Agents; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Fluorouracil; Humans; Molecular Structure; Structure-Activity Relationship; Tumor Cells, Cultured

Esophageal squamous cell carcinoma (ESCC) is one of the most intractable cancers, so the development of novel therapeutics has been required to improve patient outcomes. Curcumin, a polyphenol from Curcuma longa, exhibits various health benefits including antitumor effects, but its clinical utility is limited because of low bioavailability. Theracurmin. We examined antitumor effects of THC on ESCC cells by cell viability assay, colony and spheroid formation assay, and xenograft models. To reveal its mechanisms, we investigated the levels of reactive oxygen species (ROS) and performed microarray gene expression analysis. According to those analyses, we focused on NQO1, which involved in the removal of ROS, and examined the effects of NQO1-knockdown or overexpression on THC treatment. Moreover, the therapeutic effect of THC and NQO1 inhibitor on ESCC patient-derived xenografts (PDX) was investigated.. THC caused cytotoxicity in ESCC cells, and suppressed the growth of xenografted tumors more efficiently than curcumin. THC increased ROS levels and activated the NRF2-NMRAL2P-NQO1 expressions. Inhibition of NQO1 in ESCC cells by shRNA or NQO1 inhibitor resulted in an increased sensitivity of cells to THC, whereas overexpression of NQO1 antagonized it. Notably, NQO1 inhibitor significantly enhanced the antitumor effects of THC in ESCC PDX tumors.. These findings suggest the potential usefulness of THC and its combination with NQO1 inhibitor as a therapeutic option for ESCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Curcumin; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Hairless; Mice, Inbred C57BL; Mice, SCID; NAD(P)H Dehydrogenase (Quinone); RNA, Small Interfering; Xenograft Model Antitumor Assays

Tumor xenograft model is an indispensable animal cancer model. In esophageal squamous cell carcinoma (ESCC) research, orthotopic tumor xenograft model establishes tumor xenograft in the animal esophagus, which allows the study of tumorigenesis in its native microenvironment.. In this study,we described two simple and reproducible methods to develop tumor xenograft at the cervical or the abdominal esophagus in nude mice by direct injection of ESCC cells in the esophageal wall.. In comparing these two methods, the cervical one presented with more clinically relevant features, i.e., esophageal stricture, body weight loss and poor survival. In addition, the derived tumor xenografts accompanied a rapid growth rate and a high tendency to invade into the surrounding structures. This model was subsequently used to study the anti-tumor effect of curcumin, which is known for its potential therapeutic effects in various diseases including cancers, and its analogue SSC-5. SSC-5 was selected among the eight newly synthesized curcumin analogues based on its superior anti-tumor effect demonstrated in an MTT cell proliferation assay and its effects on apoptosis induction and cell cycle arrest in cultured ESCC cells. Treatment of orthotopic tumor-bearing mice with SSC-5 resulted in an inhibition in tumor growth and invasion.. Taken together, we have established a clinically relevant orthotopic tumor xenograft model that can serve as a preclinical tool for screening new anti-tumor compounds, e.g., SSC-5, in ESCC.

Topics: Abdomen; Animals; Catechols; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cervix Uteri; Curcumin; Drug Screening Assays, Antitumor; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Xenograft Model Antitumor Assays

We and others have previously shown that the STAT3 signaling pathway is activated in some esophageal squamous cell carcinoma (ESCC) cells and is required for the survival and growth of these primary ESCC-derived xenografts. It has also been shown that the natural polyphenol curcumin is an effective anti-tumor agent.. Luciferase assay and immunoblotting were performed to examine whether curcumin suppressed STAT3 signaling. CCK-8 assay and xenografts were utilized for analyzing ESCC cell growth in culture and mice. Soft agar assay was carried out to determine the colony formation ability of ESCC cells in the presence or absence of curcumin. Cell death and cell cycle were assessed by In CELL Analyzer 2000. Immunohistochemistry and TUNEL assay were used for detecting apoptosis in ESCC tisuses. Molecular docking was performed to evaluate the interaction of curcumin with JAK2. JAK2 activity was assessed using an in vitro cell-free system. HE staining was used to evaluate the ESCC tissues.. The natural polyphenol curcumin inhibited STAT3 phosphorylation rapidly and blocked STAT3-mediated signaling in ESCC cells. It also induced growth arrest and apoptosis in cultured ESCC cells, which were attenuated by enforced expression of STAT3. Furthermore, curcumin preferentially blocked the growth of primary ESCC-derived xenografts that harbored activated STAT3.. Curcumin is able to exert anti-tumor action through inhibiting the STAT3 signaling pathway. Giving its wide use in traditional medicines with low toxicity and few adverse reactions, it is conceivable that curcumin might be further explored as a unique STAT3 inhibitor for anti-cancer therapies.

Topics: Animals; Apoptosis; Cell Line, Tumor; Curcumin; Esophageal Squamous Cell Carcinoma; Female; Humans; Mice; Mice, SCID; Molecular Docking Simulation; Signal Transduction; STAT3 Transcription Factor; Survival Analysis; Transfection; Xenograft Model Antitumor Assays

Curcumin and its chalcone derivatives inhibit the growth of human cancer cells. It is reported that replacement of two OH groups in curcumin with less polar groups like methoxy increases its anti-proliferative activity. In this study, we explored benzylidine cyclohexanone derivatives with non-polar groups, to see if they possess increased anti-cancer activity. Novel 2,6-bis benzylidine cyclohexanone analogues of curcumin were synthesized, and their inhibitory effects on gastric adenocarcinoma (AGS) and esophageal squamous cell carcinoma (KYSE30) cancer cells were studied using an MTT assay. Cell apoptosis was detected by EB/AO staining, and cell cycle was analyzed by flow cytometry. Real-time PCR was performed for gene expression analysis. All synthesized analogues were cytotoxic toward gastric and esophageal cancer cells and showed lower IC

Topics: Adenocarcinoma; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclohexanones; Esophageal Squamous Cell Carcinoma; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Stomach Neoplasms

Curcuma zedoaria has been used as a traditional agent against malignant diseases. To elucidate detailed mechanisms producing such an activity, characterization and determination of molecular mechanisms of its antitumor effects was conducted. Inhibiting activities against cell proliferation, invasion and colony formation, and expression levels of corresponding molecules were investigated using human esophageal cancer TE-8 cells treated with the rhizome extract from C. zedoaria. Antitumor effect of the extract administered orally was also examined in tumor-bearing mice. The extract possessed strong anti-proliferation and invasion activities against TE-8 cells. Further, upregulated PTEN and downregulated phosphorylated Akt, mTOR and STAT3 expressions in the cells were induced shortly after treatment with the extract, followed by attenuation of FGFR1 and MMP-2, activation of caspase-9, caspase-3 and PARP, and suppression of Bcl-2 expressions, which led the cells to apoptotic cell death. Furthermore, tumor formation in mice was significantly suppressed through the oral administration of the extract. Taken together, these results suggest that the C. zedoaria extract could be a promising agent against esophageal cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Curcuma; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Plant Extracts; Rhizome; Xenograft Model Antitumor Assays