scholarly journals Tumour‐suppressive effect of oestrogen receptor β in colorectal cancer patients, colon cancer cells, and a zebrafish model

2020 ◽  
Vol 251 (3) ◽  
pp. 297-309
Author(s):  
Geriolda Topi ◽  
Shakti Ranjan Satapathy ◽  
Pujarini Dash ◽  
Syrina Fred Mehrabi ◽  
Roy Ehrnström ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Oestrogen Receptor ◽  
Suppressive Effect ◽  
Colon Cancer Cells ◽  
Zebrafish Model ◽  
Colorectal Cancer Patients

Clinical correlations of miR-21 expression in colorectal cancer patients and effects of its inhibition on DLD1 colon cancer cells

2012 ◽  
Vol 27 (11) ◽  
pp. 1401-1408 ◽  
Author(s):  
Petra Faltejskova ◽  
Andrej Besse ◽  
Sabina Sevcikova ◽  
Lenka Kubiczkova ◽  
Marek Svoboda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Colon Cancer Cells ◽  
Clinical Correlations ◽  
Colorectal Cancer Patients

Prognostic effects of circulating markers of epithelial mesenchymal transition (EMT) in metastatic colorectal cancer patients.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 456-456
Author(s):  
Neeraj Nailesh Shah ◽  
Christopher Hanyoung Lieu ◽  
Cristina Ivan ◽  
Michael J. Overman ◽  
Masayoshi Shimizu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Overall Survival ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Plasma Samples ◽  
Free Survival ◽  
Circulating Markers ◽  
Colorectal Cancer Patients ◽  
Circulating Levels

456 Background: EMT is a phenotypic description of cancer cells that include loss of cell adhesion, increased motility, invasion, and chemoresistance. EMT gene signature is a poor prognostic feature in colon cancer. Circulating markers to decipher the EMT signature in colorectal cancer patients (CRC pts) would therefore be of clinical relevance. Studies have shown that miR-21, IL-6 and IL-8 have been associated with EMT in cancer cells in vitro and their expression has been shown to be highly correlated in primary colon cancer tissue Methods: Plasma samples were obtained from two mCRC cohorts: 120 pts with unresectable metastases, and 91 pts who subsequently underwent partial hepatectomy with curative intent. Circulating levels of IL-6, IL-8 and miR-21 (normalized by miR-16) were measured, and dichotomized using previously published cutoffs. Pts with high levels of ≥2 of 3 EMT markers were categorized as having an EMT phenotype. Survival analysis was by log-rank and proportional hazard. Results: As previously seen in colon tissue, miR-21, IL-6 and IL-8 expression were correlated in plasma samples (P<0.001) and individually associated with shorter overall survival (P<0.05). The EMT phenotype, present in 44% of both cohorts, was a strong predictor of poor overall survival in the unresectable cohort (HR 2.6, 95% CI 1.6 to 4.1, median OS 15.5 mo v 27.1 mo, P<0.001) as well as in the validation resectable cohort(HR 3.8, 95% CI 1.9 to 7.7, median OS 41.5 mo vs 81.9 mo, P<0.001). This effect was sustained in a multivariate analysis after adjustment for tumor volume and clinical characteristics (HR 1.92, P=0.009 in unresectable cohort and HR 3.53, p=0.002 in hepatectomy cohort). The EMT phenotype was also predictive of shorter progression-free survival (HR 2.2, 15.8 mo vs 7.8 mo, P=0.02) and relapse-free survival (HR 2.1, 18.4 mo vs 31.4 mo, P=0.01) in the two respective cohorts, consistent with prior preclinical data correlating EMT with chemoresistance Conclusions: As surrogates of EMT, circulating levels of miR-21, IL-6 and IL-8 are co-expressed in plasma of mCRC pts and can be used to predict overall survival and benefit from chemotherapy. This finding highlights the clinical relevance of EMT in colon cancer biology

scholarly journals Cytotoxicity and Apoptosis Effects of Curcumin Analogue (2E,6E)-2,6-Bis(2,3-Dimethoxybenzylidine) Cyclohexanone (DMCH) on Human Colon Cancer Cells HT29 and SW620 In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1261
Author(s):  
Nurul Fattin Che Rahim ◽  
Yazmin Hussin ◽  
Muhammad Nazirul Mubin Aziz ◽  
Nurul Elyani Mohamad ◽  
Swee Keong Yeap ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Curcuma Longa ◽  
Metastatic Colon Cancer ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Sw620 Cell

Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. According to the Malaysian National Cancer Registry Report 2012–2016, colorectal cancer was the second most common cancer in Malaysia after breast cancer. Recent treatments for colon cancer cases have caused side effects and recurrence in patients. One of the alternative ways to fight cancer is by using natural products. Curcumin is a compound of the rhizomes of Curcuma longa that possesses a broad range of pharmacological activities. Curcumin has been studied for decades but due to its low bioavailability, its usage as a therapeutic agent has been compromised. This has led to the development of a chemically synthesized curcuminoid analogue, (2E,6E)-2,6-bis(2,3-dimethoxybenzylidine) cyclohexanone (DMCH), to overcome the drawbacks. This study aims to examine the potential of DMCH for cytotoxicity, apoptosis induction, and activation of apoptosis-related proteins on the colon cancer cell lines HT29 and SW620. The cytotoxic activity of DMCH was evaluated using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) cell viability assay on both of the cell lines, HT29 and SW620. To determine the mode of cell death, an acridine orange/propidium iodide (AO/PI) assay was conducted, followed by Annexin V/FITC, cell cycle analysis, and JC-1 assay using a flow cytometer. A proteome profiler angiogenesis assay was conducted to determine the protein expression. The inhibitory concentration (IC50) of DMCH in SW620 and HT29 was 7.50 ± 1.19 and 9.80 ± 0.55 µg/mL, respectively. The treated cells displayed morphological features characteristic of apoptosis. The flow cytometry analysis confirmed that DMCH induced apoptosis as shown by an increase in the sub-G0/G1 population and an increase in the early apoptosis and late apoptosis populations compared with untreated cells. A higher number of apoptotic cells were observed on treated SW620 cells as compared to HT29 cells. Human apoptosis proteome profiler analysis revealed upregulation of Bax and Bad proteins and downregulation of Livin proteins in both the HT29 and SW620 cell lines. Collectively, DMCH induced cell death via apoptosis, and the effect was more pronounced on SW620 metastatic colon cancer cells, suggesting its potential effects as an antimetastatic agent targeting colon cancer cells.

scholarly journals Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

2021 ◽  
Vol 22 (15) ◽  
pp. 8117
Author(s):  
Nunzia D’Onofrio ◽  
Elisa Martino ◽  
Luigi Mele ◽  
Antonino Colloca ◽  
Martina Maione ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

scholarly journals Antiproliferative Efficacy of N-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine, DW-8, in Colon Cancer Cells Is Mediated by Intrinsic Apoptosis

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4417
Author(s):  
Rabin Neupane ◽  
Saloni Malla ◽  
Mariam Sami Abou-Dahech ◽  
Swapnaa Balaji ◽  
Shikha Kumari ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Colon Cancer Cells ◽  
Apoptotic Pathway ◽  
Anticancer Efficacy ◽  
Colon Cell ◽  
Ic50 Values ◽  
Induced Apoptosis

A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.

scholarly journals The Anticancer Action of a Novel 1,2,4-Triazine Sulfonamide Derivative in Colon Cancer Cells

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 2045
Author(s):  
Agnieszka Gornowicz ◽  
Anna Szymanowska ◽  
Mariusz Mojzych ◽  
Robert Czarnomysy ◽  
Krzysztof Bielawski ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cathepsin B ◽  
Beclin 1 ◽  
Special Role ◽  
The Novel ◽  
Colon Cancer Cells ◽  
Sulfonamide Derivative

Cancer therapy is one of the most important challenges of modern medical and chemical sciences. Among the many methods of combating cancer, chemotherapy plays a special role. Imperfect modern chemotherapy justifies continuing the search for new, more effective, and safe drugs. Sulfonamides are the classic group of chemotherapeutic drugs with a broad spectrum of pharmacological activity. Recent literature reports show that sulfonamide derivatives have anti-tumor activity in vitro and in vivo. The aim of the study was to synthesize a novel 1,2,4-triazine sulfonamide derivative and check its anticancer potential in DLD-1 and HT-29 colon cancer cells. The biological studies included MTT assay, DNA biosynthesis, cell cycle analysis, Annexin V binding assay, ethidium bromide/acridine orange staining, and caspase-8, -9, and -3/7 activity. The concentrations of important molecules (sICAM-1, mTOR, Beclin-1, cathepsin B) involved in the pathogenesis and poor prognosis of colorectal cancer were also evaluated by ELISA. We demonstrated that the novel compound was able to induce apoptosis through intrinsic and extrinsic pathways and was capable of decreasing sICAM-1, mTOR, cathepsin B concentrations, whereas increased Beclin-1 concentration was detected in both colon cancer cell lines. The novel compound represents promising multi-targeted potential in colorectal cancer, but further in vivo examinations are needed to confirm the claim.

The orphan nuclear receptor EAR2 is overexpressed in colorectal cancer and it regulates survivability of colon cancer cells

2011 ◽  
Vol 309 (2) ◽  
pp. 137-144 ◽  
Author(s):  
Xue-bing Li ◽  
Shi Jiao ◽  
Heng Sun ◽  
Jing Xue ◽  
Wen-ting Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Nuclear Receptor ◽  
Orphan Nuclear Receptor ◽  
Colon Cancer Cells

scholarly journals Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

2016 ◽  
Vol 291 (33) ◽  
pp. 17405-17416 ◽  
Author(s):  
Yang Zhang ◽  
Yi Zhang ◽  
Liying Geng ◽  
Haowei Yi ◽  
Wei Huo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Kinase ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Mouse Xenograft Model

Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGFβ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFβ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFβ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFβ/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.

scholarly journals Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Michael Fichtner ◽  
Emir Bozkurt ◽  
Manuela Salvucci ◽  
Christopher McCann ◽  
Katherine A. McAllister ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Caspase 8 ◽  
Colon Cancer Cells ◽  
Apoptosis Pathway ◽  
Iap Antagonist

AbstractColorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells. In this study, responses to the IAP antagonist Birinapant and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell lines, representing the consensus molecular subtypes (CMS). Treatment with Birinapant alone did not result in a substantial increase in apoptotic cells in this cell line panel. Annexin-V/PI assays quantified by flow cytometry and high-content screening showed that Birinapant increased responses of CMS1 and partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not effectively sensitized. FRET-based imaging of caspase-8 and -3 activation validated these differences at the single-cell level, with CMS1 cells displaying sustained activation of caspase-8-like activity during Birinapant and oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects in combination with TNFα, suggesting that Birinapant can restore extrinsic apoptosis signaling in the context of inflammatory signals in this subtype. To explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with peripheral blood mononuclear cells. We observed increased cell death during Birinapant single treatment in these co-cultures, which was abrogated by anti-TNFα-neutralizing antibodies. Collectively, our study demonstrates that IAP inhibition is a promising modulator of response to oxaliplatin/5-FU in colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 subtype, suggesting that molecular subtyping may aid as a patient stratification tool for IAP antagonists in this disease.

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