• Asian Pacific Journal of Cancer Prevention
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• 제17권3호
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• pp.1103-1110
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• 2016

In the present study, we investigated the effects of motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed.

• BMB Reports
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• 제50권8호
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• pp.391-392
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• 2017

Overexpression of mammalian 2-Cys peroxiredoxin (Prx) enzymes is observed in most cancer tissues. Nevertheless, their specific roles in colorectal cancer (CRC) progression has yet to be fully elucidated. Here, a novel molecular mechanism by which PrxII/Tankyrase (TNKS) interaction mediates survival of adenomatous polyposis coli (APC)-mutant CRC cells was explored. In mice with an inactivating APC mutation, a model of spontaneous intestinal tumorigenesis, deletion of PrxII reduced intestinal adenomatous polyposis and thereby increased survival. In APC-mutant human CRC cells, PrxII depletion hindered PARP-dependent Axin1 degradation through TNKS inactivation. $H_2O_2-sensitive$ Cys residues in the zinc-binding domain of TNKS1 was found to be crucial for PARsylation activity. Mechanistically, direct binding of PrxII to ARC4/5 domains of TNKS conferred vital redox protection against oxidative inactivation. As a proof-of-concept experiment, a chemical compound targeting PrxII inhibited the growth of tumors xenografted with APC-mutation-positive CRC cells. Collectively, the results provide evidence revealing a novel redox mechanism for regulating TNKS activity such that physical interaction between PrxII and TNKS promoted survival of APC-mutant colorectal cancer cells by PrxII-dependent antioxidant shielding.

• Journal of Ginseng Research
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• 제40권4호
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• pp.400-408
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• 2016

Background: Ginsenoside Rh2 (GRh2) is the main bioactive component in American ginseng, a commonly used herb, and its antitumor activity had been studied in previous studies. PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK), a serine/threonine protein kinase, is highly expressed in HCT116 colorectal cancer cells. Methods: We examined the effect of GRh2 on HCT116 cells ex vivo. Next, we performed in vitro binding assay and in vitro kinase assay to search for the target of GRh2. Furthermore, we elucidated the underlying molecular mechanisms for the antitumor effect of GRh2 ex vivo and in vivo. Results: The results of our in vitro studies indicated that GRh2 can directly bind with PBK/TOPK and GRh2 also can directly inhibit PBK/TOPK activity. Ex vivo studies showed that GRh2 significantly induced cell death in HCT116 colorectal cancer cells. Further mechanistic study demonstrated that these compounds inhibited the phosphorylation levels of the extracellular regulated protein kinases 1/2 (ERK1/2) and (H3) in HCT116 colorectal cancer cells. In vivo studies showed GRh2 inhibited the growth of xenograft tumors of HCT116 cells and inhibited the phosphorylation levels of the extracellular regulated protein kinases 1/2 and histone H3. Conclusion: The results indicate that GRh2 exerts promising antitumor effect that is specific to human HCT116 colorectal cancer cells through inhibiting the activity of PBK/TOPK.

• Biomolecules & Therapeutics
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• 제23권2호
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• pp.134-140
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• 2015

Conjugated linoleic acids (CLA) are a family of isomers of linoleic acid. CLA increases growth arrest and apoptosis of human colorectal cancer cells through an isomer-specific manner. ATF3 belongs to the ATF/CREB family of transcription factors and is associated with apoptosis in colorectal cancer. The present study was performed to investigate the molecular mechanism by which t10, c12-CLA stimulates ATF3 expression and apoptosis in human colorectal cancer cells. t10, c12-CLA increased an apoptosis in human colorectal cancer cells in dose dependent manner. t10, c12-CLA induced ATF3 mRNA and luciferase activity of ATF3 promoter in a dose-dependent manner. The responsible region for ATF3 transcriptional activation by t10, c12-CLA is located between -147 and -1850 of ATF3 promoter. mRNA stability of ATF3 was not affected by t10, c12-CLA treatment. t10, c12-CLA increases $GSK3{\beta}$ expression and suppresses IGF-1-stimulated phosphorylation of Akt. The knockdown of ATF3 suppressed expression of $GSK3{\beta}$ and NAG-1 and PARP cleavage. The results suggest that t10, c12-CLA induces apoptosis through ATF3-mediated pathway in human colorectal cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• 제14권11호
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• pp.6791-6795
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• 2013

Apoptotic and cytotoxic activity of plant extracts obtaining from naturally growing Cynara syriaca in Turkey and cultivated C cardunculus against DLD1 colorectal cancer cells was determined. Extracts from wild and cultivated Cynara species were obtained from their vegetative parts and receptacles using hexane and applied with five different dose (0.1-1 mg/ml) as well as apigenin for MTT tests for three time periods (24, 48 and 72 hours). After cells were treated with $IC_{50}$ doses for each extract total DNA and RNA were isolated for determination of the cause of cell death. From isolated RNAs, cDNA were synthesized and amplification of p21, BCL-2 and BAX gene regions was carried out. Consequently, we found that pro-apoptotic (BAX) gene expression and a cell cycle inhibitor (p21) were induced in the presence of our artichoke extracts. In contrast, anti-apoptotic BCL-2 gene expression was reduced compared to the control group. In addition DNA fragmentation results demonstrated DLD1 cell death via apoptosis.

• Biomolecules & Therapeutics
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• 제24권4호
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• pp.380-386
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• 2016

Silymarin from milk thistle (Silybum marianum) has been reported to show an anti-cancer activity. In previous study, we reported that silymarin induces cyclin D1 proteasomal degradation through NF-${\kappa}B$-mediated threonine-286 phosphorylation. However, mechanism for the inhibition of Wnt signaling by silymarin still remains unanswered. Thus, we investigated whether silymarin affects Wnt signaling in human colorectal cancer cells to elucidate the additional anti-cancer mechanism of silymarin. Transient transfection with a TOP and FOP FLASH luciferase construct indicated that silymarin suppressed the transcriptional activity of ${\beta}$-catenin/TCF. Silymarin treatment resulted in a decrease of intracellular ${\beta}$-catenin protein but not mRNA. The inhibition of proteasome by MG132 and $GSK3{\beta}$ inhibition by SB216763 blocked silymarin-mediated downregulation of ${\beta}$-catenin. In addition, silymarin increased phosphorylation of ${\beta}$-catenin and a point mutation of S33Y attenuated silymarin-mediated ${\beta}$-catenin downregulation. In addition, silymarin decreased TCF4 and increased Axin expression in both protein and mRNA level. From these results, we suggest that silymarin-mediated downregulation of ${\beta}$-catenin and TCF4 may result in the inhibition of Wnt signaling in human colorectal cancer cells.

• 한국한의학연구원논문집
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• 제17권2호
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• pp.129-134
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• 2011

Objective : The purpose of this study was to investigate the anti-cancer effects of Carthami Flos in some kinds of human colorectal adenocarcinoma cells. Method : We used two kinds of human colorectal adenocarcinoma cell lines, such as HT-29 and WiDr cells. We examined cell death by MTT assay and observed the morphological changes with Carthami Flos. Result : We showed that the combination of sub-optimal doses of Carthami Flos and cisplatin noticeably suppresses in HT-29 cells and doxorubicin in WiDr cells. Furthermore, we studied the caspase 3 activity to identify the apoptosis. Conclusion : Our findings provide insight into unraveling the effects of Carthami Flos in human colorectal adenocarcinoma cells and developing therapeutic agents against colorectal cancer.

• Journal of Digestive Cancer Research
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• 제6권1호
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• pp.11-15
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• 2018

Chemotherapy and surgical resection are the mainstay of cancer treatment. Particularly for chemotherapy, although it is effective method to care, sometimes cure various cancers, there are many different status of cancer not being controlled by chemotherapy such as recurrence and resistance to chemotherapy. In order to overcome those difficulties during cancer therapy, immunotherapy targeting immune cells and immune associated factors to enhance cancer immunity has been highlighted. Innate immunity plays important roles on initial stage of cancer immunity that are detecting, killing cancer cells and initiating adaptive immunity for cancer. So many basic and clinical studies to manage innate immunity for cancer therapy have been going on, and most of them were to stimulate innate immune cells including dendritic cell, macrophage, monocyte, and natural killer cell in various ways. They showed promising results but still there are many things to be resolved before clinical application. Herein, I review the role of innate immune cells and therapeutic trials for colorectal cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제16권2호
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• pp.565-570
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• 2015

Breast and colorectal cancers rank high in Iran as causes of mortality. Most of the current treatments are expensive and non-specific. The potential anticancer properties of common home gecko, Cyrtopodion scabrum, were investigated in this study. The effects of C. scabrum extract on proliferation, viability and migration of the colorectal cancer (SW-742), breast cancer (MCF-7) and normal (MSC) cell lines were investigated using MTT and in vitro wound healing assay. $IC_{50}$ values calculated for the extract were $559{\pm}28.9{\mu}g/mL$ for MCF-7 and $339{\pm}11.3{\mu}g/mL$ for SW-742. No toxic effects on the normal control cells were observed. MCF-7 and SW-742 cell growth was inhibited by 32.6% and 62%, under optimum conditions, compared to the untreated control cells. The extract also decreased the motility and migration ability of both cancer cell lines, with no significant effects on the normal control cells. Data suggest C. scabrum extract as a useful natural resource for targeting cancer cells specifically.

• 대한의생명과학회지
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• 제18권1호
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• pp.16-21
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• 2012

Although there are many potential cytotoxic molecules released from bacteria, the role of these molecules on the apoptosis of various cancer cells is not well understood. Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative, aerobic and rod-shaped bacterium, and has a number of virulence factors. To understand the cytotoxic effect of bacterial extracts on the colorectal cancer cell line, HCT 116 cells, we examined alteration of the cell viability, proliferation, cell cycle and apoptosis of HCT 116 cells after treatment with extract of P. aeruginosa (PaE). These cytotoxicity of PaE occurred in a time- and a dose-dependent manners. In addition, PaE arrested the cell cycle of HCT 116 cell in a time-dependent manner. PaE inhibited the protein levels of Bcl-2 and induced the release of cytochrome c from mitochondria of HCT 116 cells. The decrease of procaspase-3 was induced by the treatment of PaE. These results indicate that PaE has a cytotoxicity in HCT 116 cells via the induction of apoptosis associated with mitochondrial pathway. Therefore, PaE may used as the potential target for the treatment of colorectal cancer.