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

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.

Download Full-text

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

Molecules ◽

10.3390/molecules26237375 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7375

Author(s):

Paulina Lewandowska ◽

Izabela Szczuka ◽

Iwona Bednarz-Misa ◽

Berenika M. Szczęśniak-Sięga ◽

Katarzyna Neubauer ◽

...

Keyword(s):

Colorectal Cancer ◽

Colorectal Adenocarcinoma ◽

Normal Mucosa ◽

Colorectal Tumors ◽

Adjacent Tissue ◽

Inflammatory Drug ◽

Chemokine Expression ◽

Adenocarcinoma Cells ◽

Thiazine Ring ◽

N Stage

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.

Download Full-text

Effects of maternal l-citrulline supplementation on renal function and blood pressure in offspring exposed to maternal caloric restriction: The impact of nitric oxide pathway

Nitric Oxide ◽

10.1016/j.niox.2010.03.005 ◽

2010 ◽

Vol 23 (1) ◽

pp. 34-41 ◽

Cited By ~ 60

Author(s):

You-Lin Tain ◽

Chih-Sung Hsieh ◽

I-Chun Lin ◽

Chih-Cheng Chen ◽

Jiunn-Ming Sheen ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Renal Function ◽

Caloric Restriction ◽

The Impact ◽

Nitric Oxide Pathway

Download Full-text

High expression of Wnt7a protein predicts a poor survival in patients with colorectal carcinoma

10.21203/rs.3.rs-19428/v1 ◽

2020 ◽

Author(s):

Congcong Li ◽

Peilin Cui ◽

Xiaowei Dou ◽

Hongli Li ◽

Jiahuan Sun ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Malignant Tumors ◽

Integration Site ◽

Normal Mucosa ◽

Lymph Node Involvement ◽

Colorectal Adenomas ◽

Future Research ◽

Colorectal Mucosa ◽

Staining Score

Abstract Background: Colorectal cancer is one of the most common malignant tumors in China, and the number of new cases and the number of cases of deaths has increased annually. However, its pathogenesis is still unclear. Wnt7a is a member of the wingless-type MMTV integration site family, and it plays an important role in tumorigenesis and development by controlling cell proliferation and differentiation as a secreted glycoprotein. Whether Wnt7a has the properties of an oncogene or not is an important focus for future research as this target has diverse roles in different tumors.Methods: Wnt7a protein expression in normal colorectal mucosa and colorectal tumors was detected via immunohistochemistry and Western blot analysis. Univariate and multivariate analyses were used to explore the associations between Wnt7a staining score and various clinical parameters.Results: Wnt7a was strongly expressed in colorectal cancer tissues but weakly expressed in adjacent normal mucosa and colorectal adenomas. The level of Wnt7a expression was correlated with lymph node involvement (P < 0.001), Duke stage (P < 0.001), and cell differentiation (P < 0.001). Knockdown of Wnt7a inhibits proliferation of colon cancer cells and inhibits the ability of both colon cancer cell lines to migrate.Conclusions: Collectively, our results present evidence that Wnt7a is associated with an unfavorable prognosis of colorectal cancer.

Download Full-text

Synchronous brain metastasis and impact of primary tumor side in colorectal cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.712 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 712-712

Author(s):

Mahvish Muzaffar ◽

Abdul Rafeh Naqash

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Brain Metastasis ◽

Regression Model ◽

Primary Tumor ◽

Tumor Grade ◽

Hepatic Flexure ◽

Female Ratio ◽

Cancer Tumor ◽

The Impact

712 Background: 25% of patients with colorectal cancer(CRC) present with synchronous metastatic disease. The incidence of brain metastasis (BM) in CRC is very low (1.2–3.2%) and tend to occur later in the disease course. Synchronous BM(SBM) in CRC is very rare. We sought to explore the impact of primary tumor characteristics on SBM. Methods: Surveillance Epidemiology End Results Program (SEER) 18 registries research data on primary colorectal cancer cases diagnosed during 2010-2015 with brain metastasis at diagnosis were identified. Patients with unlabeled primary site and autopsy alone cases were excluded. Demographic and colorectal cancer characteristics including age, gender, race, tumor grade and primary tumor side were analyzed. Logistic regression model was used to test the association between survival and side of cancer. Results: A total of 475 cases met the inclusion criteria. The mean age was 64.04 yrs. (range 28-95). Majority of the patients (80%) were white, 12% black and others (8%), Male: Female ratio was 1:1.58% patients had primary tumor on left side (splenic flexure, sigmoid, rectosigmoid and rectal) and 42% had right sided (ascending colon, hepatic flexure, cecum, transverse colon) primary tumor. The median overall survival was 5 months with 1-year survival of 26% in the whole cohort. The 1-year overall survival was 21% for patients with right sided primary tumor versus 30% for patients with SBM and left sided primary tumor(p = 0.03). The median disease specific survival was 5 months for right side and 7 months for Left sided tumor with SBM. The regression model showed that higher grade (RR 14, p = 0.003)) and right sided primary tumor (RR 4.2, p = 0.04) were associated with worse outcome among patients with SBM in colorectal cancer. Conclusions: Synchronous brain metastasis is very rare in colorectal cancer. Tumor side seems to be prognostic even in this aggressive disease subset. This differential outcome further indicates that sidedness should be considered in goals of care and treatment discussion.

Download Full-text

Clinical and biologic factors associated with time to progression in patients treated by first-line palliative FOLFOX chemotherapy in metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14159 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14159-e14159

Author(s):

Wieslaw Bal ◽

Michal Jarzab ◽

Ewa Stobiecka ◽

Jadwiga Zebracka ◽

Marta Mianowska ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Lymph Node ◽

Tumor Grade ◽

Lymph Node Involvement ◽

Time To Progression ◽

First Line ◽

Node Involvement ◽

Grade 3 ◽

Folfox Chemotherapy

e14159 Background: Chemotherapy is the mainstay of treatment patients with metastatic colorectal cancer. The choice of first-line treatment is difficult, especially when cost-effectiveness is the primary constraint. Thus, the optimal use of the clinical and biological factors influencing prognosis would be beneficial. The aim of our study was to identify factors affecting the time to progression (TTP) after first-line FOLFOX chemotherapy in palliative setting. Methods: The study is a retrospective analysis of the series of consecutive patients from large cancer center in south of Poland. The analysis was carried out in the group of 180 patients (37.2% of women), treated between 2007-2010 by FOLFOX-4 regimen and followed-up with the median time of observation 16.3 month. Patients received chemotherapy with median time of 5.0 months, median 10 cycles. Progression was defined as PD by RECIST criteria, death due to disease or sympomatic deterioration. 94 paraffin blocks were available for KRAS testing and gene expression analysis by real-time PCR. Results: The median TTP (counted from beginning of chemotherapy) was 8.6 month, the median TTP from the end of treatment was 3.4 month. We tested the wide range of clinical variables associated with both disease and and patient status by multivariate Cox regression analysis. Two most potent independent negative predictors were identified: the presence of massive lymph node involvement as assessed in CT scan before palliative treatment (>10 nodes enlarged) – hazard ratio 2.82, p<0.001; and tumor grade in histopathological assessment (grade 3 vs. grade 1-2) – hazard ratio 2.76, p=0.003. KRAS status was not prognostic for the TTP; Ki67 gene expression measurement by quantitative RT-PCR did not predict better that the routine assessment of grade. Patients with either grade 3 or lymph node involvement showed significantly shorter TTP (median 5.7 months vs 9.7 months in patients with none of these factors). Conclusions: High tumor grade and the massive involvement of lymph nodes worsen prognosis and shorten time to progression in patients treated with first line palliative FOLFOX chemotherapy.

Download Full-text

The impact of biologic agents in patients with metastatic colorectal cancer by race/ethnicity.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.156 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 156-156

Author(s):

Seda Serra Tolu ◽

Adel Chergui ◽

Devika Rao ◽

Meghan Kaumaya ◽

Ana Acuna-Villaorduna ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Ethnic Groups ◽

Survival Benefit ◽

Tumor Grade ◽

Biologic Agents ◽

Biologic Agent ◽

Race Ethnicity ◽

The Impact ◽

Racial Ethnic

156 Background: Biologic agents have shown to improve overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, minority racial/ethnic groups were underrepresented in clinical trials. A retrospective study in a racially-diverse population diagnosed between 2000 - 2011, done by our group, reported a survival benefit with biologics; but, a subgroup analysis suggested that it was restricted to Non-Hispanic whites (NHW) only. This study aims to compare OS in patients with mCRC treated with chemotherapy and biologic agents (CBT) among racial/ethnic groups. Methods: Patients diagnosed with mCRC between 2012-2018 and treated with CBT at 3 cancer centers in the Bronx, NY were identified. Clinical data was collected by retrospective review for demographics (age at metastasis, gender and race/ethnicity categorized as Non-hispanic Black (NHB), NHW or Hispanic), pathological/ treatment characteristics (tumor grade, primary location, chemotherapy regimen, biologic agent). Cases without available race/ethnicity were excluded. OS was measured as time from mCRC diagnosis to death (verified from the National Death Index) and was compared among racial/ethnic groups using Kaplan-Meier curves. Results: A total of 278 patients; of whom 84 (42.4%) were Hispanic, 70 (35.4%) NHB and 44 (22.2%) NHW were included. The median age at diagnosis was 60 years and did not differ among racial/ethnic groups (62.5 vs 55.5 vs 56 years, p=0.07). There was a female predominance in NHB and Hispanics. Bevacizumab was more frequently used in Hispanics and NHB compared to NHW (95.2% vs. 92.9% vs. 77.3%, p=0.003, respectively). There were no differences in the frequency of cetuximab and panitumumab use. Median OS did not differ by racial/ethnic groups (21 in NHW vs. 22.8 in Hispanics and 28.6 months in NHB, p=0.40). Conclusions: Minority groups attain a similar survival benefit from the addition of biologics compared to NHW. Population-based studies are required to confirm these results.

Download Full-text