Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer

The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.

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L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs

Cancers ◽

10.3390/cancers12092594 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2594 ◽

Cited By ~ 1

Author(s):

Małgorzata Krzystek-Korpacka ◽

Berenika Szczęśniak-Sięga ◽

Izabela Szczuka ◽

Paulina Fortuna ◽

Marek Zawadzki ◽

...

Keyword(s):

Nitric Oxide ◽

Colorectal Cancer ◽

Tumor Grade ◽

Normal Mucosa ◽

Lymph Node Involvement ◽

Metabolic Reprogramming ◽

Adjacent Tissue ◽

Thiazine Ring ◽

The Impact ◽

Nitric Oxide Pathway

L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine’s and piperazine’s nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.

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The activity of antioxidant enzymes in colorectal adenocarcinoma and corresponding normal mucosa.

Acta Biochimica Polonica ◽

10.18388/abp.2012_2090 ◽

2012 ◽

Vol 59 (4) ◽

Cited By ~ 11

Author(s):

Joanna Katarzyna Strzelczyk ◽

Tomasz Wielkoszyński ◽

Łukasz Krakowczyk ◽

Brygida Adamek ◽

Marzena Zalewska-Ziob ◽

...

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Superoxide Dismutase ◽

Antioxidant Enzymes ◽

Glutathione Peroxidase ◽

Colorectal Adenocarcinoma ◽

Average Distance ◽

Normal Mucosa ◽

Colorectal Carcinogenesis ◽

Tissue Homogenates

Oxidative stress is one of several factors which contribute to the development of colorectal carcinogenesis. The aim of the study was an assessment of the activity of antioxidant enzymes in tumour and corresponding normal distal mucosa in a group of patients with colorectal adenocarcinoma. Samples of tumour and corresponding normal mucosa were obtained during a resection of colorectal cancer from 47 patients aged between 26 and 82 years. The average distance of corresponding normal distal mucosa from the tumour was 4.49 cm. Activities of antioxidant enzymes: superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione S-transferase (GST), and catalase (CAT) were measured in tissue homogenates. The patients were grouped according to the tumour stage (Duke's staging), grading, localization, and size of tumour, as well as age and sex. Statistical analysis was performed. The activity of SOD and GPx was considerably increased, while the activity of GST decreased significantly in tumour as compared with normal mucosa. GR activity in colorectal cancer was evidently higher in tumours of proximal location compared with the distal ones. The distance of corresponding normal distal mucosa from the tumour was analyzed and related to all assayed parameters. A decreased GST activity was observed in corresponding normal mucosa more than 5 cm distant from the tumour in patients with CD Duke's stage. The higher activity of superoxide dismutase and glutathione peroxidase in tumour compared to corresponding normal mucosa could indicate higher oxidative stress in colorectal adenocarcinoma cells.

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A serine protease extracted from Trichosanthes kirilowii induces apoptosis via the PI3K/AKT-mediated mitochondrial pathway in human colorectal adenocarcinoma cells

Food & Function ◽

10.1039/c5fo00760g ◽

2016 ◽

Vol 7 (2) ◽

pp. 843-854 ◽

Cited By ~ 14

Author(s):

Li Song ◽

Jiao Chang ◽

Zhuoyu Li

Keyword(s):

Colorectal Cancer ◽

Serine Protease ◽

Colorectal Adenocarcinoma ◽

Mitochondrial Pathway ◽

Adenocarcinoma Cells ◽

Trichosanthes Kirilowii ◽

Dependent Pathway ◽

Cancer Activity ◽

Novel Protein

A novel protein TKP extracted from T. kirilowii fruit exerted potential anti-colorectal cancer activity by inducing apoptosis, which was regulated by the PI3K/AKT-mediated mitochondria-dependent pathway.

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The levels of sICAM-1, sELAM-1, TNFα and sTNFR1 proteins in patients with colorectal adenocarcinoma in tumor and corresponding normal mucosa

Acta Biochimica Polonica ◽

10.18388/abp.2020_5449 ◽

2020 ◽

Author(s):

Joanna K. Strzelczyk ◽

Piotr Cuber ◽

Benjamin Bochon ◽

Krzysztof Gajdzik ◽

Janusz Strzelczyk ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Colorectal Adenocarcinoma ◽

Cancer Survival ◽

Distant Metastases ◽

Normal Mucosa ◽

Protein Levels ◽

Tissue Homogenates ◽

Clinical Profiles ◽

Tissue Specimens

Colorectal cancer is a common malign disease of the gastrointestinal tract. The cancer survival rate depends on the stage of the disease at detection time. It is well known that several molecular mechanisms are involved in cancer and some molecules might affect or modulate neogenesis. The aim of the study was to assess the levels of sICAM-1, sELAM-1, TNFα and sTNFR1 protein in tumor and corresponding normal mucosa in a group of patients with colorectal adenocarcinoma and also associations of these parameters with demographic and clinical profiles of the patients. Tissue specimens were obtained during resection of neoplastic lesions. Protein levels were assayed in tissue homogenates by ELISA. The protein level of sICAM-1 in tumor was significantly increased in comparison to the corresponding normal mucosa (80.06 ng/mg vs 69.53 ng/mg, p=0.02). Furthermore, a significant positive correlation between sICAM-1 and sTNFR1 proteins levels in tumor (rs=0.58, p<0.001) and in corresponding normal mucosa (rs=0.48, p<0.001) was found. Also, significant correlations in corresponding normal mucosa were found between sELAM-1 and sICAM-1 (rs=0.58, p<0.001) and between sTNFR1 and sELAM-1 (rs=0.57, p<0.001). Significantly higher level of sTNFR1 in corresponding normal mucosa samples of patients with distant metastases was observed (p=0.04). Obtained results suggest that sICAM-1 protein could be considered as colorectal cancer marker. Furthermore, sTNFR1 also has the potential to become a good prognostic marker used during monitoring of the patients. Nevertheless, a further study in this area to confirm this correlation is required.

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Expression of HER2 in Colorectal Cancer Does Not Correlate with Prognosis

Disease Markers ◽

10.1155/2010/109063 ◽

2010 ◽

Vol 29 (5) ◽

pp. 207-212 ◽

Cited By ~ 22

Author(s):

Wiesław Janusz Kruszewski ◽

Robert Rzepko ◽

Maciej Ciesielski ◽

Jarosław Szefel ◽

Jacek Zieliński ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Membrane ◽

Predictive Factor ◽

Colorectal Adenocarcinoma ◽

Prognostic Significance ◽

Staining Intensity ◽

Her2 Expression ◽

Prognostic Information ◽

Adenocarcinoma Cells ◽

Entire Cell

Estimation of HER2 membranous expression is routinely used in breast and gastric cancers, as both a prognostic and a predictive factor. To date there is no evidence for similar application of HER2 expression in colorectal cancer (CRC) cells. In CRC, HER2 is sometimes overexpressed in the cell membrane and very often in the cytoplasm. This study was conducted to determine possible correlations between both membranous and cytoplasmatic expression of HER2 in CRC cells and the outcome of the disease. The prognostic significance of combined staining intensity in the cell membrane and cytoplasm in the entire CRC cell was also investigated. HER2 expression in resectable colorectal adenocarcinoma cells was evaluated by immunohistochemistry in specimens taken from 202 patients. The percentage of cancer cells with membranous or cytoplasmatic reactions and the staining intensity of the reaction in the whole cell were recorded. A membranous reaction was present in 27% of cases, and cytoplasmatic reaction in 66% of cases. The total staining intensity in the entire cell was evaluated as moderate (2+) in 32% of cases and strong (3+) staining in 15%. There was no correlation found between either membranous or cytoplasmatic HER2 expression and survival. Furthermore combined staining intensity did not provide any prognostic information. We conclude that HER2 expression in CRC does not correlate with prognosis.

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Serum DJ-1 Is a Biomarker of Colorectal Cancer and DJ-1 Activates Mitophagy to Promote Colorectal Cancer Progression

Cancers ◽

10.3390/cancers13164151 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4151

Author(s):

William Tzu-Liang Chen ◽

Han-Bin Yang ◽

Tao-Wei Ke ◽

Wen-Ling Liao ◽

Shih-Ya Hung

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Cancer Cell ◽

Cancer Progression ◽

Colorectal Adenocarcinoma ◽

Reactive Oxygen Species Generation ◽

Cancer Drug ◽

Adenocarcinoma Cells ◽

Colorectal Cancer Progression ◽

Colorectal Cancer Patients

Colorectal cancer is the second most common cancer and the third cancer-associated death in Taiwan. Currently used serum markers for detecting colorectal cancer lack excellent diagnostic accuracy, which results in colorectal cancer being often recognized too late for successful therapy. Mitophagy is the selective autophagic degradation of damaged or excessive mitochondria. DJ-1 is an antioxidant protein that attenuates oxidative stress and maintains mitochondrial quality through activating mitophagy. Mitophagy activation contributes to anti-cancer drug resistance. However, the role of DJ-1-induced mitophagy in colorectal cancer progression remains unclear. In the present study, we collected matched tumor and adjacent normal tissues and serum from patients and cancer cells to demonstrate the clinical value and physiological function of DJ-1 in colorectal cancer. We found that DJ-1 increased in tumor tissues and serum; it was positively correlated with TNM (tumor-node-metastasis) stages of colorectal cancer patients. Through stable knockdown DJ-1 expression in metastatic colorectal adenocarcinoma cells SW620, DJ-1 knockdown inhibited cancer cell survival, migration, and colony formation. In SW620 cells, DJ-1 knockdown induced an incomplete autophagic response that did not affect ATP production; DJ-1 knockdown enhanced intracellular reactive oxygen species generation and damaged mitochondrial accumulation and mitophagy inhibition. It suggests that DJ-1 knockdown inhibits mitophagy that causes metastatic colorectal adenocarcinoma cells to be unable to remove damaged mitochondria and further enhance cancer cell apoptosis. Our data indicate that DJ-1 might be clinically valuable as serum and tissue biomarkers for predicting the TNM stage in colorectal cancer patients. Since DJ-1-induced mitophagy promotes tumor progression, DJ-1 inhibition is a potential therapeutic strategy for colorectal cancer treatment.

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The fatty acid derivative palmitoylcarnitine abrogates colorectal cancer cell survival by depleting glutathione

AJP Cell Physiology ◽

10.1152/ajpcell.00319.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. C1278-C1288 ◽

Cited By ~ 2

Author(s):

Patrick C. Turnbull ◽

Meghan C. Hughes ◽

Christopher G. R. Perry

Keyword(s):

Colorectal Cancer ◽

Cell Survival ◽

Cancer Cell ◽

Colorectal Adenocarcinoma ◽

Breast Adenocarcinoma ◽

Mcf7 Cells ◽

Ht29 Cells ◽

Adenocarcinoma Cells ◽

Hct 116 ◽

The Relationship

Previous evidence suggests that palmitoylcarnitine incubations trigger mitochondrial-mediated apoptosis in HT29 colorectal adenocarcinoma cells, yet nontransformed cells appear insensitive. The mechanism by which palmitoylcarnitine induces cancer cell death is unclear. The purpose of this investigation was to examine the relationship between mitochondrial kinetics and glutathione buffering in determining the effect of palmitoylcarnitine on cell survival. HT29 and HCT 116 colorectal adenocarcinoma cells, CCD 841 nontransformed colon cells, and MCF7 breast adenocarcinoma cells were exposed to 0 μM, 50 μM, and 100 μM palmitoylcarnitine for 24–48 h. HCT 116 and HT29 cells showed decreased cell survival following palmitoylcarnitine compared with CCD 841 cells. Palmitoylcarnitine stimulated H2O2 emission in HT29 and CCD 841 cells but increased it to a greater level in HT29 cells due largely to a higher basal H2O2 emission. This greater H2O2 emission was associated with lower glutathione buffering capacity and caspase-3 activation in HT29 cells. The glutathione-depleting agent buthionine sulfoximine sensitized CCD 841 cells and further sensitized HT29 cells to palmitoylcarnitine-induced decreases in cell survival. MCF7 cells did not produce H2O2 when exposed to palmitoylcarnitine and were able to maintain glutathione levels. Furthermore, HT29 cells demonstrated the lowest mitochondrial oxidative kinetics vs. CCD 841 and MCF7 cells. The results demonstrate that colorectal cancer is sensitive to palmitoylcarnitine due in part to an inability to prevent oxidative stress through glutathione-redox coupling, thereby rendering the cells sensitive to elevations in H2O2. These findings suggest that the relationship between inherent metabolic capacities and redox regulation is altered early in response to palmitoylcarnitine.

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ADAM-17/FHL2 colocalisation suggests interaction and role of these proteins in colorectal cancer

Tumor Biology ◽

10.1177/1010428317695024 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769502 ◽

Cited By ~ 2

Author(s):

Laurine Verset ◽

Joke Tommelein ◽

Christine Decaestecker ◽

Elly De Vlieghere ◽

Marc Bracke ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Lines ◽

Cancer Progression ◽

Colorectal Adenocarcinoma ◽

Normal Mucosa ◽

Scaffolding Protein ◽

Proximity Ligation Assay ◽

Low Grade ◽

Proximity Ligation ◽

Sw480 Cells

FHL2 is a multifunctional scaffolding protein; its expression is associated with poor prognosis in colorectal cancer. ADAM-17 is a metalloprotease implicated in ectodomain shedding. FHL2 regulates ADAM-17 plasma membrane localisation, and FHL2 deficiency leads to decreased activity of ADAM-17 in mouse macrophages. Presence and relationship of the ADAM-17/FHL2 complex with colorectal cancer progression is unknown. We studied FHL2 and ADAM-17 expression in several colon cancer cell lines by immunocytochemistry and western blot. To highlight the interaction between both molecules, we used the Duolink® kit for proximity ligation assay on SW480 cells. We also performed proximity ligation assay on biopsies and surgical specimens of colorectal adenocarcinoma and on matched normal mucosa. Furthermore, biopsies of colorectal adenoma with matched normal mucosa were selected. For quantification, pictures of the malignant, adenomatous and normal tissues were taken. Proximity ligation assay signals were quantified. Mean numbers of proximity ligation assay signals and of proximity ligation assay signals/nucleus were calculated. All cell lines showed FHL2 immunoreactivity; strongest positivity was observed in SW480 cells. ADAM-17 was expressed in all cell lines. Proximity ligation assay signals were present in SW480 cells. Quantitative analysis revealed that the interaction between FHL2 and ADAM-17 is more frequent in malignant than in normal tissue (p = 0.005). The mean number of ADAM-17/FHL2 proximity ligation assay signals was higher in colorectal adenocarcinoma than in adenoma with low-grade dysplasia (p = 0.0004). FHL2 interacts with ADAM-17 in normal, dysplastic and malignant colon epithelial cells. Colocalisation of these proteins is more frequent in malignant than in normal and dysplastic cells, suggesting a role for ADAM-17/FHL2 complex in the development of colorectal cancer.

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The relationship between p53, Bcl2 proteins and histological grade in colorectal adenocarcinoma associated with type 2 diabetes and obesity

Proceedings of The Nutrition Society ◽

10.1017/s0029665120005753 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Popescu-Vâlceanu Horaţiu-Cristian ◽

Stoicea Mihai ◽

Enache Valentin ◽

Mustatea Petronel ◽

Rusu Emilia ◽

...

Keyword(s):

Colorectal Cancer ◽

Colorectal Adenocarcinoma ◽

Histological Grade ◽

P53 Protein ◽

Diabetic Patients ◽

Reference Laboratory ◽

Low Grade ◽

Colorectal Tumors ◽

Type 2 Diabetic

AbstractIntroductionThe aim of our study was to evaluate the expression of p53 protein in colorectal adenocarcinoma in diabetic (type 2) obese vs non-obese vs and to analyse p53, Bcl2 proteins expression in type 2 diabetic vs non-diabetic patients based on histological grade.Material and MethodsIn a retrospective study we analyzed all hospitalized patients with colorectal cancer between 2011–2015 in Bucharest Emergency Hospital, according to International Statistical Classification of Diseases classification and Related Health Problems 10th Revision.The p53 and Bcl2 proteins expressions were investigated by automated immunohistochemistry BenchMark XT Ventana platform using dual Bcl2-p53 protocol in the Histopathology Department of the Central Reference Laboratory Synevo.ResultsWe identified in order of appearance only the cases with appropriate inclusion criteria, 95 cases of colorectal adenocarcinoma: 52 were type 2 diabetic patients (33males /19 females, mean age 70.2 years) and 43 non-diabetics (30 males /13 females mean age 69.5 years). There were 15vs2 obese subjects in diabetic/non-diabetic patients compared to 37vs41 with normal weight.Our data showed that obese diabetic patients associate more frequently the overexpression of p53 protein in colorectal adenocarcinoma in the 80% (12/15 of cases) comparative with non-obese diabetic patients 40.5% (15/37 cases) or non-diabetics and non-obese controls 36.6% (15/41 cases p = 0.024).Regarding histological grade, diabetic patients associated low-grade colorectal tumors (78.8% of cases) compared with non-diabetics (58.1% of cases) and non-diabetic patients associated high-grade colorectal tumors increased (41.9%) compared to diabetics (21.2%), with statistical significance (p = 0.043).Diabetics compared with non-diabetics associated an oversexpression of all immunophenotypes in the low histological grade colorectal adenocarcinoma: Bcl2-/p53- immunophenotype in 62% vs 53% of cases (p = 0.836); for Bcl2 + / p53- immunophenotype in 67% vs 43% of cases (p = 0.064); for Bcl2-/p53 + immunophenotype in 77% vs 71% of cases (p = 0.489) and for Bcl2 + /p53 + immunophenotype in 100% vs33% of cases (p = 0.333).DiscussionIt is known that the protein p53 is a powerful transcriptor factor acting as checkpoint controlling the differentiation of the various cells including adipocytes and also possible enterocytes (explaining the higher frequency of colorectal cancer which has been associated with the increased proliferation of adipocytes characterizing the obesity).Due to the protection conferred by a normal p53 protein its upregulation could be a new target for the treatment of obesity. Interesting our work revealed that diabetic patients associated low-grade colorectal adenocarcinoma with an oversexpression of all immunophenotypes.

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Ideal 1:1 stoichiometry curcumin inclusion complex induced potential apoptosisin colorectal adenocarcinoma cells: The clear image of necrosis and functionalized dying effect

Current Signal Transduction Therapy ◽

10.2174/1574362414666190625125838 ◽

2019 ◽

Vol 14 ◽

Author(s):

Kavitha K ◽

Muthu Mohamed J ◽

Chitra Karthikeyini S

Keyword(s):

Colorectal Cancer ◽

Cell Death ◽

Cell Growth ◽

Inclusion Complex ◽

Colorectal Adenocarcinoma ◽

Phase Solubility ◽

Adenocarcinoma Cell ◽

Adenocarcinoma Cells ◽

Ic50 Value ◽

Hot Melt

Background: This study investigates the inclusion complex of curcumin (CMN) enhance the solubility, which can be utilized for the treatment of colorectal cancer (CRC) greater to free CMN. Methods: CMN solid dispersion (SD) prepared by a hot melt method using CMN with several carriers of poloxamers (P-407 and P-188), gelucire 50/13 (GLR) and mannitol (MNT). Prior, molecular modelling and phase solubility studieswere performed with drug and carriers. The SD characterized by in vitrodrug release, SEM and functionalize dyeing test. Additionally, the cytotoxicity and image of apoptosisresolved to utilize the colorectal adenocarcinoma cell lines. Results: The result showed that CMN-P-407 inclusion complex produced significant properties towards solubility (318 ± 14.46 fold) and dissolution (91 ± 0.431% at 30 min). Similarly, these data fit with insilico model. The IC50 value for inclusion complex found to be 74 and 52 µM/mL, while that for free CMN ranged from 146 and 116 µM/mL on the SW480 and Caco-2 cells respectively. Apoptosis study described that the cells are undergoing cell death by apoptosis and the small number of necrosis. Conclusion: The profound efﬁciency of CMN-P-407 SD indicated its potential application for CRC treatment by showing a higher capability of inhibiting cell growth compared to that of free CMN.

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