scholarly journals Targeted Nanoparticle Photodynamic Diagnosis and Therapy of Colorectal Cancer

2021 ◽  
Vol 22 (18) ◽  
pp. 9779
Author(s):  
Nokuphila Winifred Nompumelelo Simelane ◽  
Cherie Ann Kruger ◽  
Heidi Abrahamse
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cultured Cells ◽  
Zinc Phthalocyanine ◽  
Photodynamic Diagnosis ◽  
Tumor Cell Death ◽  
Aggressive Cancer ◽  
Alternative Techniques ◽  
High Range

Colorectal cancer (CRC) is an aggressive cancer that remains a challenge to diagnose and treat. Photodynamic diagnosis (PDD) and therapy (PDT) are novel alternative techniques, which can enhance early diagnosis, as well as elicit tumor cell death. This is accomplished through photosensitizer (PS) mediated fluorescence and cytotoxic reactive oxygen species activation upon laser light irradiation excitation at specific low and high range wavelengths, respectively. However, the lack of PS target tumor tissue specificity often hampers these techniques. This study successfully fabricated a bioactive nanoconjugate, ZnPcS4-AuNP-S-PEG5000-NH2-Anti-GCC mAb (BNC), based upon a polyethylene glycol-gold nanoparticle, which was multi-functionalized with a fluorescent PDT metalated zinc phthalocyanine PS, and specific anti-GCC targeting antibodies, to overcome CRC PDD and PDT challenges. The BNC was found to be stable and showed selectively improved subcellular accumulation within targeted CRC for improved PDD and PDT outcomes in comparison to healthy in vitro cultured cells. Additionally, the BNC reported significantly higher late apoptotic PDT-induced CRC cell death rates (34% ***) when compared to PDT PS administration alone (15% *). These results indicated that the improved PDD and PDT outcomes were due to the specific PS accumulation in CRC cells through nanoparticle carriage and bioactive anti-GCC targeting.

scholarly journals Multiorganelle Localization of Metallated Phthalocyanine Photosensitizer in Colorectal Cancer Cells (DLD-1 and CaCo-2) Enhances Efficacy of Photodynamic Therapy

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Palesa Rose Sekhejane ◽  
Nicolette Nadene Houreld ◽  
Heidi Abrahamse
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Photodynamic Therapy ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Annexin V ◽  
Zinc Phthalocyanine ◽  
Cell Death Pathway

Colorectal cancer is the third most commonly diagnosed cancer. Amongst treatments that have been explored, photodynamic therapy (PDT) is a treatment that is of interest as it poses ideal advantages such as affinity for cancer cells. This study aimed to determine the correlation between the localization site of a sulfonated zinc phthalocyanine (ZnPcSmix) photosensitizer (PS) and its associated cell death pathwayin vitroin colorectal cancer cell lines (DLD-1 and CaCo-2). Visible morphological changes were observed in PDT treated cells after 24 h. Reactive oxygen species (ROS) were detected and visualized 1 h after PDT.ZnPcSmixwas predominantly localized in lysosomes and partially in the mitochondria. FITC Annexin V staining showed a significant decrease in the percentage of viable DLD-1 and CaCo-2 cells 24 h after PDT, with an increase in apoptotic cell population. Moreover, there was a significant increase in both cathepsin D and cytochrome C at 1 and 24 h. In conclusion,ZnPcSmixshowed the ability of inducing apoptotic cell death features in PDT treated cells.

scholarly journals YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Lan Jin ◽  
Yunhe Chen ◽  
Dan Cheng ◽  
Zhikai He ◽  
Xinyi Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Transcriptional Coactivator ◽  
Inhibitory Protein ◽  
Potential Therapeutic Target ◽  
Related Cell ◽  
Autophagy Inhibition

AbstractColorectal cancer (CRC) is one of the most aggressive and lethal cancers. The role of autophagy in the pathobiology of CRC is intricate, with opposing functions manifested in different cellular contexts. The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor-suppressor pathway, functions as an oncoprotein in a variety of cancers. In this study, we found that YAP could negatively regulate autophagy in CRC cells, and consequently, promote tumor progression of CRC in vitro and in vivo. Mechanistically, YAP interacts with TEAD forming a complex to upregulate the transcription of the apoptosis-inhibitory protein Bcl-2, which may subsequently facilitate cell survival by suppressing autophagy-related cell death; silencing Bcl-2 expression could alleviate YAP-induced autophagy inhibition without affecting YAP expression. Collectively, our data provide evidence for YAP/Bcl-2 as a potential therapeutic target for drug exploration against CRC.

Photodynamic Therapy with Liposomal Zinc Phthalocyanine and Tirapazamine Increases Tumor Cell Death via DNA Damage

2017 ◽  
Vol 13 (2) ◽  
pp. 204-220 ◽  
Author(s):  
Mans Broekgaarden ◽  
Ruud Weijer ◽  
AlbertC. van Wijk ◽  
RuudC. Cox ◽  
MaartenR. Egmond ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Photodynamic Therapy ◽  
Tumor Cell ◽  
Zinc Phthalocyanine ◽  
Tumor Cell Death

scholarly journals Overexpression of IRS-4 Correlates with Procaspase 3 Levels in Tumoural Tissue of Patients with Colorectal Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-14
Author(s):  
Patricia Sanmartín-Salinas ◽  
Luis G. Guijarro
Keyword(s):  
Colorectal Cancer ◽  
Caspase 3 ◽  
Cultured Cells ◽  
Cyclin Dependent Kinase ◽  
Kinase Activation ◽  
Tnm System ◽  
Protein Levels ◽  
Receptor Signalling ◽  
T Values

We reported that insulin receptor substrate 4 (IRS-4) levels increased in tissue from colorectal cancer (CRC) patients and promoted retinoblastoma-cyclin-dependent kinase activation. The aim of the present study was to evaluate the effect of IRS-4 on IGF-1 receptor pathway and its impact on procaspase 3 and PARP expression in RKO and HepG2 cancer cell lines. The results obtained in vitro were compared with those obtained from biopsies of patients with CRC (n = 18), tubulovillous adenomas (TA) (n = 2) and in matched adjacent normal colorectal (MANC) tissue (n = 20). IRS-4 overexpression in cultured cells induced the overactivation of IGF-1/BRK/AKT/GSK-3/β-catenin/cyclin D1 pathways, which led to increased expression of procaspase 3 and PARP protein levels. Studies carried out on CRC and TA tissues revealed the overactivation of the IGF-1 receptor signalling pathway, as well as the overexpression of procaspase 3 and PARP in tumoural tissue with respect to MANC tissue. The upregulation of IRS-4 in tumoural samples correlated significantly with the increase in pIGF-1 receptor (Tyr 1165/1166) (r = 0.84; p < 0.0001), procaspase 3 (r = 0. 77; p < 0. 0005) and PARP (r = 0. 89; p < 0. 0005). Similarly, we observed an increase in the proteolysis of procaspase 3 in tumoural tissue with respect to MANC tissue, which correlated significantly with the degradation of PARP (r = 0.86; p < 0.0001), p53 (r = 0.84; p < 0.0001), and GSK-3 (r = 0.78; p < 0.0001). The stratification of patient samples using the TNM system revealed that procaspase 3 and caspase 3 increased gradually with T values, which suggests their involvement in the size and local invasion of primary tumours. Taken together, our findings suggest that IRS-4 overexpression promotes the activation of the IGF-1 receptor pathway, which leads to the increase in procaspase 3 levels in CRC.

scholarly journals Tumor cell death visualization of renal cell carcinoma under the combined effect of the Gratiola officinalis extract and cyclophosphamide using fluorescent staining methods

2021 ◽  
pp. 2142004
Author(s):  
Artyom Mylnikov ◽  
Nikita Navolokin ◽  
Dmitry Mudrak ◽  
Natalya Polukonova ◽  
Alla Bucharskaya ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Human Kidney ◽  
Combined Effect ◽  
Tumor Cell Death ◽  
Staining Methods ◽  
Apoptotic Activity ◽  
Apoptosis And Necrosis ◽  
Number Of Cells

Objective of the study: We used fluorescence imaging methods of apoptosis and necrosis in human renal carcinoma A498 tumor cells in vitro to reveal the indicated forms of cell death under the combined effect of flavonoid-containing extract of Gratiola officinalis and cytostatic (cyclophosphamide). Materials and methods: The dyes were propidium iodide and acridine orange, which were used in the “alive and dead” test. This test helped us to identify the total number of dead cells in the forms of necrosis and apoptosis and the number of cells in which apoptosis had started, it was characterized by the appearance of apoptotic bodies or nucleus pyknosis. Results: We found the most pronounced cytotoxic activity at the ratio of extract of Gratiola officinalis and cyclophosphamide concentrations of 1:1. The number of living cells decreased when exposed to the ratio of extract and cytostatic concentrations of 2:1. When the ratio of concentration of the extract relative to the cytostatic increased to 3:1, the cytostatic activity of the extract began to appear, the total number of tumor cells decreased. The number of cells with nucleus pyknosis and the number of cells with apoptosis signs significantly increased at a 3:1 ratio of extract and cytostatic concentrations, which confirms the presence of pro-apoptotic activity of the studied combination. This trend indicates the dependence of a certain form of cell death (apoptosis, necrosis) on the ratio of extract and cytostatic doses, and it also demonstrates the cytostatic and cytotoxic effects of this combination. Conclusion: Fluorescence methods of investigation in the “alive and dead” test allowed us to visualize the forms of cell death of human kidney carcinoma A498 by combined exposure to the flavonoid-containing extract of Gratiola officinalis and cytostatic (cyclophosphamide) 24 h after exposure. We found that the combination with a concentration ratio of the extract and cyclophosphamide of 3:1 has the greatest effectiveness due to stimulation of the cytostatic effect and cytotoxic effect.

scholarly journals O8 Gemcitabine induces pro-apoptotic BH3 only proteins and sensitizes pancreatic ductal adenocarcinoma cells for RLH-triggered immunogenic cell death

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A7.1-A7
Author(s):  
P Metzger ◽  
HT Bourhis ◽  
M Stieg ◽  
D Böhmer ◽  
S Endres ◽  
...  
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Tumor Cell ◽  
Single Agent ◽  
Ductal Adenocarcinoma ◽  
Immunogenic Cell Death ◽  
Tumor Cell Death ◽  
Antigen Uptake ◽  
Cross Presentation

BackgroundDespite tremendous effort, the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) remains poor and therapy options are limited. Recent advances in chemotherapeutic schemes have increased the survival of PDAC patients by a few months only. So far, the success of immunotherapy seen in other cancer types could not be transferred to PDAC. Our group has demonstrated that single agent RIG-I-like helicase (RLH)-targeting immunotherapy induces an anti-tumoral immune response and improves survival in a PDAC mouse model dependent on the induction of immunogenic cell death. In addition, we and others were able to show that tumor cell death induction by RLH ligands is partially dependent on the induction of the pro-apoptotic BH3-only proteins PUMA and NOXA. In the current study we aim at improving therapy response using a combinatorial chemo-immunotherapy (CIT) approach.MethodsTumor cell death induction by gemcitabine, oxaliplatin and 5-fluoruracil (5-FU) alone or in combination with RLH ligands was evaluated in the murine cell line Panc02. The induction of PUMA and NOXA was measured by real-time PCR. The capability of chemo-immunotherapy -induced tumor cell death to activate splenic CD8a+dendritic cells (DC) as well as to induce antigen uptake and cross-presentation was investigated in vitro. Therapeutic efficacy was evaluated in vivo using an orthotopic PDAC mouse model.ResultsGemcitabine, oxaliplatin and 5-FU induced dose-dependent tumor cell death in vitro. however, only gemcitabine lead to an induction of the pro-apoptotic proteins PUMA and NOXA. Simultaneous treatment with gemcitabine and RLH-ligand increased cell death induction without affecting the cytokine secretion substantially. CD8a+ DC activation upon RLH-therapy was not affected by chemotherapy. Of note, antigen uptake as well as T cell priming was increased by chemo-immunotherapy. Most importantly, the survival of orthotopic PDAC bearing mice was significantly prolonged in the chemo-immunotherapy group compared to single agent treatment.ConclusionsGemcitabine treatment of PDAC induces PUMA and NOXA expression which leads to mitochondrial priming and sensitization towards RLH-induced cell death. chemo-immunotherapy increases the cross-presentation capability of DC in vitro and prolongs the survival of PDAC bearing mice. chemo-immunotherapy is therefore an attractive combinatorial therapeutic approach in PDAC.FundingThe project was supported by the Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 179062510 and 329628492 - SFB 1321 as well as the Förderprogramm für Forschung und Lehre (FöFoLe) funded by the Ludwig-Maximilians-Universität München.Disclosure InformationP. Metzger: None. H.T. Bourhis: None. M. Stieg: None. D. Böhmer: None. S. Endres: None. P. Düwell: None. L.M. König: None. M. Schnurr: None.

Parvovirus H-1-Induced Tumor Cell Death Enhances Human Immune Response In Vitro via Increased Phagocytosis, Maturation, and Cross-Presentation by Dendritic Cells

2005 ◽  
Vol 0 (0) ◽  
pp. 050701034702004
Author(s):  
Markus H. Moehler ◽  
Maja Zeidler ◽  
Vanessa Wilsberg ◽  
Jan J. Cornelis ◽  
Thomas Woelfel ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Dendritic Cells ◽  
Tumor Cell ◽  
Tumor Cell Death ◽  
Cross Presentation ◽  
Human Immune Response ◽  
Human Immune ◽  
Immune Response In Vitro

scholarly journals Dominant-negative ATF5 rapidly depletes survivin in tumor cells

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Xiaotian Sun ◽  
James M. Angelastro ◽  
David Merino ◽  
Qing Zhou ◽  
Markus D. Siegelin ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Dominant Negative ◽  
Tumor Cell Death ◽  
Cell Penetrating ◽  
Selective Death ◽  
Tumor Types

Abstract Survivin (BIRC5, product of the BIRC5 gene) is highly expressed in many tumor types and has been widely identified as a potential target for cancer therapy. However, effective anti-survivin drugs remain to be developed. Here we report that both vector-delivered and cell-penetrating dominant-negative (dn) forms of the transcription factor ATF5 that promote selective death of cancer cells in vitro and in vivo cause survivin depletion in tumor cell lines of varying origins. dn-ATF5 decreases levels of both survivin mRNA and protein. The depletion of survivin protein appears to be driven at least in part by enhanced proteasomal turnover and depletion of the deubiquitinase USP9X. Survivin loss is rapid and precedes the onset of cell death triggered by dn-ATF5. Although survivin downregulation is sufficient to drive tumor cell death, survivin over-expression does not rescue cancer cells from dn-ATF5-promoted apoptosis. This indicates that dn-ATF5 kills malignant cells by multiple mechanisms that include, but are not limited to, survivin depletion. Cell-penetrating forms of dn-ATF5 are currently being developed for potential therapeutic use and the present findings suggest that they may pose an advantage over treatments that target only survivin.

scholarly journals Mitoxantrone-Loaded Nanoparticles for Magnetically Controlled Tumor Therapy–Induction of Tumor Cell Death, Release of Danger Signals and Activation of Immune Cells

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 923
Author(s):  
Teresa Ratschker ◽  
Laura Egenberger ◽  
Magdalena Alev ◽  
Lisa Zschiesche ◽  
Julia Band ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune System ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Superparamagnetic Iron Oxide ◽  
Dependent Manner ◽  
Tumor Cell Death ◽  
Immune Therapies

Stimulating the patient’s immune system represents a promising therapeutic strategy to fight cancer. However, low immunogenicity of the tumor cells within an immune suppressive milieu often leads to weak anti-tumor immune responses. Additionally, the immune system may be impaired by accompanying aggressive chemotherapies. We show that mitoxantrone, bound to superparamagnetic iron oxide nanoparticles (SPIONs) as the transport system, can be magnetically accumulated in adherent HT-29 colon carcinoma cells, thereby inducing the same cell death phenotype as its soluble counterpart, a chemotherapeutic agent and prototypic inductor of immunogenic cell death. The nanoparticle-loaded drug induces cell cycle stop, apoptosis and secondary necrosis in a dose- and time-dependent manner comparable to the free drug. Cell death was accompanied by the release of interleukin-8 and damage-associated molecular patterns (DAMPs) such as HSP70 and ATP, which fostered chemotactic migration of monocytes and maturation of dendritic cells. We furthermore ensured absence of endotoxin contaminations and compatibility with erythrocytes and platelets and investigated the influence on plasma coagulation in vitro. Summarizing, with magnetic enrichment, mitoxantrone can be accumulated at the desired place, sparing healthy peripheral cells and tissues, such as immune cells. Conserving immune competence in cancer patients in the future might allow combined therapeutic approaches with immune therapies (e.g., checkpoint inhibitors).

scholarly journals Inhibition of microRNA-21 via locked nucleic acid-anti-miR suppressed metastatic features of colorectal cancer cells through modulation of programmed cell death 4

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769226 ◽  
Author(s):  
Reza Nedaeinia ◽  
Mohammadreza Sharifi ◽  
Amir Avan ◽  
Mohammad Kazemi ◽  
Abdolreza Nabinejad ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Polymerase Chain Reaction ◽  
Cell Death ◽  
Nucleic Acid ◽  
Locked Nucleic Acid ◽  
Chain Reaction ◽  
Programmed Cell Death 4 ◽  
Polymerase Chain ◽  
Novel Therapeutic

Colorectal cancer is among the most lethal of malignancies, due to its propensity to metastatic spread and multifactorial-chemoresistance. The latter property supports the need to identify novel therapeutic approaches for the treatment of colorectal cancer. MicroRNAs are endogenous non-coding small RNA molecules that function as post-transcriptional regulators of gene expression. Recently, programmed cell death 4 has been identified as a protein that increases during apoptosis. This gene is among the potential targets of miR-21 (OncomiR). Locked nucleic acid–modified oligonucleotides have recently emerged as a potential therapeutic option for targeting microRNAs. The aim of this study was to explore the functional role of locked nucleic acid-anti-miR-21 in the LS174T cell line in vitro and in vivo models. LS174T cells were treated with locked nucleic acid-anti-miR-21 for 24, 48, and 72 h in vitro. The expression of miR-21 and PDCD4 at messenger RNA (mRNA) level was evaluated by quantitative real-time polymerase chain reaction, while the protein level of PDCD4 was determined by Western blotting. Cell migratory behavior and the cluster-forming ability of cells were assessed before and after therapy. The disseminated tumor cells were assessed in the chick chorioallantoic membrane model by Alu quantitative polymerase chain reaction. Locked nucleic acid-anti-miR-21 was transfected successfully into the LS174T cells and inhibited the expression of miR-21. Locked nucleic acid-anti-miR-21 inhibited the migration and the number of cells forming clusters. Moreover, we found that locked nucleic acid-anti-miR-21 transfection was associated with a significant reduction in metastatic properties as assessed by the in ovo model. Our findings demonstrated the novel therapeutic potential of locked nucleic acid-anti-miR-21 in colon adenocarcinoma with high miR-21 expression.

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