scholarly journals Design, Synthesis, and Cytotoxicity Assessment of [64Cu]Cu-NOTA-Terpyridine Platinum Conjugate: A Novel Chemoradiotherapeutic Agent with Flexible Linker

Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2154
Author(s):  
Meysam Khosravifarsani ◽  
Samia Ait-Mohand ◽  
Benoit Paquette ◽  
Léon Sanche ◽  
Brigitte Guérin
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Human Fibroblasts ◽  
Fold Increase ◽  
Radiation Energy ◽  
Design Synthesis ◽  
Quadruplex Dna ◽  
Low Energy Electrons ◽  
Normal Human

Maximum benefits of chemoradiation therapy with platinum-based compounds are expected if the radiation and the drug are localized simultaneously in cancer cells. To optimize this concomitant effect, we developed the novel chemoradiotherapeutic agent [64Cu]Cu-NOTA-C3-TP by conjugating, via a short flexible alkyl chain spacer (C3), a terpyridine platinum (TP) moiety to a NOTA chelator complexed with copper-64 (64Cu). The decay of 64Cu produces numerous low-energy electrons, enabling the 64Cu-conjugate to deliver radiation energy close to TP, which intercalates into G-quadruplex DNA. Accordingly, the in vitro internalization kinetic and the cytotoxic activity of [64Cu]Cu-NOTA-C3-TP and its derivatives were investigated with colorectal cancer (HCT116) and normal human fibroblast (GM05757) cells. Radiolabeling by 64Cu results in a >55,000-fold increase of cytotoxic potential relative to [NatCu]Cu-NOTA-C3-TP at 72 h post administration, indicating a large additive effect between 64Cu and the TP drug. The internalization and nucleus accumulation of [64Cu]Cu-NOTA-C3-TP in the HCT116 cells were, respectively, 3.1 and 6.0 times higher than that for GM05757 normal human fibroblasts, which is supportive of the higher efficiency of the [64Cu]Cu-NOTA-C3-TP for HCT116 cancer cells. This work presents the first proof-of-concept study showing the potential use of the [64Cu]Cu-NOTA-C3-TP conjugate as a targeted chemoradiotherapeutic agent to treat colorectal cancer.

scholarly journals Synthesis of 4-thio-5-(2′′-thienyl)uridine and cytotoxicity activity against colon cancer cells in vitro

RSC Advances ◽  
2016 ◽  
Vol 6 (74) ◽  
pp. 70099-70105 ◽  
Author(s):  
Xiaohui Zhang ◽  
Depeng Li ◽  
Jianzhong Qin ◽  
Yaozhong Xu ◽  
Kedong Ma
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Human Fibroblasts ◽  
Antiproliferative Effect ◽  
Colon Cancer Cells ◽  
Cytotoxicity Activity ◽  
Normal Human ◽  
Ht 29

Antiproliferative effect of 4-thio-5-(2′′-thienyl)uridine on MC-38 cells, HT-29 cells and normal human fibroblasts cells.

scholarly journals Study of Synergistic and Protective Effects of Three Different Polar Saffron Extracts and Photon Radiation on Human Colorectal Cancer Cells (HT-29) and Normal Human Fibroblasts

2020 ◽  
Vol 13 (12) ◽  
Author(s):  
Mahnaz Nourbakhsh ◽  
Amin Hosseinzade ◽  
Jamshidkhan Chamani ◽  
Ameneh Sazgarnia ◽  
Roham Salek
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Human Fibroblasts ◽  
Protective Effects ◽  
Normal Cells ◽  
Colorectal Cancer Cells ◽  
Normal Human ◽  
Saffron Extract ◽  
Ht 29

Background: There are some hypotheses about radiation-sensitizing and radiation-protective effects of antioxidants. Saffron, dried stigmas of Crocus sativus L., is a precious medicinal plant that contains an impressive variety of plant compounds such as crocin, crocetin, and safranal that act as antioxidants. The present study examined the cytotoxic effects of saffron extracts with different polarity and their synergism or protective effects with radiation on a colorectal cancer cell line (HT-29) and normal human fibroblasts. Objectives: The aim was to find a natural agent to improve radiotherapy efficacy. Methods: HT-29 colorectal cancer cells and normal human fibroblasts were cultured in RPMI1640 medium, incubated with different concentrations of different saffron extracts (50-250 µg/ml), and then were exposed to a dose of 8 Gy of X-rays. The cytotoxicity effect was determined by the MTT assay. Results: Saffron extracts decreased cell viability in HT-29 colorectal cancer cells and normal human fibroblasts as a concentration-dependent manner. Combination radiotherapy with polar saffron extract in most doses showed synergistic effects on HT-29 cell death while it did not show any distinctive synergistic effect in normal cells. Semi-polar and non-Polar extracts just in low doses had synergistic effects on tumor cells. These two extracts did not show any protective effects on normal cells. Conclusions: Among the various saffron extracts, polar saffron extract and low doses of non-polar saffron extract in combination with radiation increase radiation sensitivity and cell death in tumor cells, while they do not increase radiation sensitivity in normal cells and even protect normal cells to some extent.

scholarly journals Pals1 prevents Rac1-dependent colorectal cancer cell metastasis by inhibiting Arf6

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Simona Mareike Lüttgenau ◽  
Christin Emming ◽  
Thomas Wagner ◽  
Julia Harms ◽  
Justine Guske ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Scaffolding Protein ◽  
Migration And Invasion ◽  
Tight Junction Formation ◽  
Cell Metastasis ◽  
Colorectal Cancer Cells

AbstractLoss of apical-basal polarity and downregulation of cell-cell contacts is a critical step during the pathogenesis of cancer. Both processes are regulated by the scaffolding protein Pals1, however, it is unclear whether the expression of Pals1 is affected in cancer cells and whether Pals1 is implicated in the pathogenesis of the disease.Using mRNA expression data and immunostainings of cancer specimen, we show that Pals1 is frequently downregulated in colorectal cancer, correlating with poorer survival of patients. We further found that Pals1 prevents cancer cell metastasis by controlling Rac1-dependent cell migration through inhibition of Arf6, which is independent of the canonical binding partners of Pals1. Loss of Pals1 in colorectal cancer cells results in increased Arf6 and Rac1 activity, enhanced cell migration and invasion in vitro and increased metastasis of transplanted tumor cells in mice. Thus, our data reveal a new function of Pals1 as a key inhibitor of cell migration and metastasis of colorectal cancer cells. Notably, this new function is independent of the known role of Pals1 in tight junction formation and apical-basal polarity.

scholarly journals Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Changhong Li ◽  
Kui Zhang ◽  
Guangzhao Pan ◽  
Haoyan Ji ◽  
Chongyang Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Growth ◽  
Er Stress ◽  
Cancer Cells ◽  
Tumor Xenograft ◽  
Anticancer Activities ◽  
Colorectal Cancer Cells

Abstract Background Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

scholarly journals Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 MPro Inhibitor

2021 ◽  
Vol 14 (6) ◽  
pp. 541
Author(s):  
Hani A. Alhadrami ◽  
Ahmed M. Sayed ◽  
Heba Al-Khatabi ◽  
Nabil A. Alhakamy ◽  
Mostafa E. Rateb
Keyword(s):  
Binding Free Energy ◽  
Human Fibroblasts ◽  
Critical Time ◽  
Dynamics Simulation ◽  
Direct Access ◽  
Energy Calculation ◽  
Wide Range ◽  
Normal Human ◽  
Novel Scaffold

The COVID-19 pandemic is still active around the globe despite the newly introduced vaccines. Hence, finding effective medications or repurposing available ones could offer great help during this serious situation. During our anti-COVID-19 investigation of microbial natural products (MNPs), we came across α-rubromycin, an antibiotic derived from Streptomyces collinus ATCC19743, which was able to suppress the catalytic activity (IC50 = 5.4 µM and Ki = 3.22 µM) of one of the viral key enzymes (i.e., MPro). However, it showed high cytotoxicity toward normal human fibroblasts (CC50 = 16.7 µM). To reduce the cytotoxicity of this microbial metabolite, we utilized a number of in silico tools (ensemble docking, molecular dynamics simulation, binding free energy calculation) to propose a novel scaffold having the main pharmacophoric features to inhibit MPro with better drug-like properties and reduced/minimal toxicity. Nevertheless, reaching this novel scaffold synthetically is a time-consuming process, particularly at this critical time. Instead, this scaffold was used as a template to explore similar molecules among the FDA-approved medications that share its main pharmacophoric features with the aid of pharmacophore-based virtual screening software. As a result, cromoglicic acid (aka cromolyn) was found to be the best hit, which, upon in vitro MPro testing, was 4.5 times more potent (IC50 = 1.1 µM and Ki = 0.68 µM) than α-rubromycin, with minimal cytotoxicity toward normal human fibroblasts (CC50 > 100 µM). This report highlights the potential of MNPs in providing unprecedented scaffolds with a wide range of therapeutic efficacy. It also revealed the importance of cheminformatics tools in speeding up the drug discovery process, which is extremely important in such a critical situation.

105 A third-generation human GUCY2C-targeted CAR-T cell for colorectal cancer immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A116-A116
Author(s):  
Trevor Baybutt ◽  
Adam Snook ◽  
Scott Waldman ◽  
Jonathan Stem ◽  
Ellen Caparosa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cancer Cells ◽  
Inflammatory Cytokines ◽  
Department Of Defense ◽  
Thomas Jefferson ◽  
Third Generation ◽  
Car T Cells ◽  
Car T

BackgroundColorectal cancer (CRC) presents a significant public health burden, responsible for the second most cancer-related deaths in the United States, with an increasing incidence in young adults observed globally.1,2 While the blockade of immune checkpoints received FDA approval as a CRC therapeutic, only patients with microsatellite instability, accounting for 15% of sporadic cases, demonstrate partial or complete responses.3 We present a third-generation chimeric antigen receptor (CAR)-T cell directed towards the extracellular domain of the mucosal antigen guanylyl cyclase C (GUCY2C), which is over-expressed in 80% of CRC cases, as a therapeutic alternative for late stage disease. Here, we demonstrate that human GUCY2C CAR-T cells can selectively kill GUCY2C-expressing colorectal cancer cells in vitro and produce inflammatory cytokines in response to antigenic stimulation.MethodsPeripheral blood mononuclear (PBMCs) cells were isolated from leukoreduction filters obtained from the Thomas Jefferson University Hospital Blood Donor Center (IRB #18D.495). Magnetic Activated Cell Sorting (MACS) technology was used to negatively select pan-T cells (Miltenyi Biotec), followed by activation and expansion using anti-CD3, anti-CD28, and anti-CD2 coated microbeads (Miltenyi Biotec) and supplemented with IL-7 and IL-15 (Biological Resources Branch Preclinical Biologics Repository – NCI). T-cells were transduced with a lentiviral vector encoding the anti-GUCY2C CAR. Our CAR utilizes a single chain variable fragment of human origin directed towards the extracellular domain of GUCY2C, the CD28 hinge, transmembrane, and intracellular signaling domain (ICD), 4-1BB (CD137) ICD, and CD3ζ ICD. CAR-T cells were used for experiments between 10 to 14 days after activation in vitro using the xCELLigence real time cytotoxicity assay and intracellular cytokine staining.ResultsGUCY2C-directed CAR-T cells specifically lysed the GUCY2C-expressing metastatic CRC cell line T84, while the control CAR did not. GUCY2C-negative CRC cells were not killed by either. In addition to cell killing, GUCY2C-directed CAR-T cells of both the CD8+ and CD4+ co-receptor lineage produced the inflammatory cytokines IFN-γ and TNFα in response to GUCY2C antigen.ConclusionsWe demonstrate that human GUCY2C-directed CAR-T cells can selectively target GUCY2C-expressing cancer cells. We hypothesize that GUCY2C-directed CAR-T cells present a viable therapeutic option for metastatic CRC. In vivo animal models to examine this potential are currently on-going.AcknowledgementsThis work was supported by the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-17-1-0299, W81XWH-191-0263, and W81XWH-19-1-0067) to AES and Targeted Diagnostic & Therapeutics to SAW. AES is also supported by a DeGregorio Family Foundation Award. SAW is supported by the National Institutes of Health (NIH) (R01 CA204881, R01 CA206026, and P30 CA56036), and the Department of Defense Congressionally Directed Medical Research Program W81XWH-17-PRCRP-TTSA. SAW and AES were also supported by a grant from The Courtney Ann Diacont Memorial Foundation. SAW is the Samuel M.V. Hamilton Professor of Thomas Jefferson University. JS, EC, and AZ were supported by an NIH institutional award T32 GM008562 for Postdoctoral Training in Clinical Pharmacology.Ethics ApprovalThis study was approved by the Thomas Jefferson University Institutional Review Board (IRB Control #18D.495) and the Institutional Animal Care and Use Committee (Protocol #01529).ReferencesSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin2020;70: 7–30. doi:10.3322/caac.21590Araghi M, Soerjomataram I, Bardot A, Ferlay J, Cabasag CJ, Morrison DS, et al. Changes in colorectal cancer incidence in seven high-income countries: a population-based study. Lancet Gastroenterol Hepatol 2019;4: 511–518. doi:10.1016/S2468-1253(19)30147-5Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz H-J, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017;18: 1182–1191. doi:10.1016/S1470-2045(17)30422-9

scholarly journals MicroRNA-124 Regulates the Proliferation of Colorectal Cancer Cells by TargetingiASPP

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Kuijie Liu ◽  
Hua Zhao ◽  
Hongliang Yao ◽  
Sanlin Lei ◽  
Zhendong Lei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Target Prediction ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Small Noncoding Rnas ◽  
Colorectal Cancer Cells ◽  
Microrna 124

MicroRNAs are a class of small, noncoding RNAs that function as critical regulators of gene expression by targeting mRNAs for translational repression or degradation. In this study, we demonstrate that expression of microRNA-124 (miR-124) is significantly downregulated in colorectal cancer tissues and cell lines, compared to the matched adjacent tissues. We identified and confirmed inhibitor of apoptosis-stimulating protein of p53 (iASPP) as a novel, direct target of miR-124 using target prediction algorithms and luciferase reporter gene assays. Overexpression of miR-124 suppressed iASPP protein expression, upregulated expression of the downstream signaling molecule nuclear factor-kappa B (NF-κB), and attenuated cell viability, proliferation, and colony formation in SW480 and HT-29 colorectal cancer cells in vitro. Forced overexpression ofiASPPpartly rescued the inhibitory effect of miR-124 on SW480 and HT29 cell proliferation. Taken together, these findings shed light on the role and mechanism of action of miR-124, indicate that the miR-124/iASPP axis can regulate the proliferation of colorectal cancer cells, and suggest that miR-124 may serve as a potential therapeutic target for colorectal cancer.

scholarly journals Human Endogenous Retrovirus (HERV)-K env Gene Knockout Affects Tumorigenic Characteristics of nupr1 Gene in DLD-1 Colorectal Cancer Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 3941
Author(s):  
Eun-Ji Ko ◽  
Mee-Sun Ock ◽  
Yung-Hyun Choi ◽  
Juan L. Iovanna ◽  
Seyoung Mun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Gene Knockout ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Ros Generation ◽  
Nude Mouse Model ◽  
Env Protein

Human endogenous retroviruses (HERVs) are suggested to be involved in the development of certain diseases, especially cancers. To elucidate the function of HERV-K Env protein in cancers, an HERV-K env gene knockout (KO) in DLD-1 colorectal cancer cell lines was generated using the CRISPR-Cas9 system. Transcriptome analysis of HERV-K env KO cells using next-generation sequencing (NGS) was performed to identify the key genes associated with the function of HERV-K Env protein. The proliferation of HERV-K env KO cells was significantly reduced in in vitro culture as well as in in vivo nude mouse model. Tumorigenic characteristics, including migration, invasion, and tumor colonization, were also significantly reduced in HERV-K env KO cells. Whereas, they were enhanced in HERV-K env over-expressing DLD-1 cells. The expression of nuclear protein-1 (NUPR1), an ER-stress response factor that plays an important role in cell proliferation, migration, and reactive oxygen species (ROS) generation in cancer cells, significantly reduced in HERV-K env KO cells. ROS levels and ROS-related gene expression was also significantly reduced in HERV-K env KO cells. Cells transfected with NUPR1 siRNA (small interfering RNA) exhibited the same phenotype as HERV-K env KO cells. These results suggest that the HERV-K env gene affects tumorigenic characteristics, including cell proliferation, migration, and tumor colonization through NUPR1 related pathway.

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