Pro-oxidant drugs have been proposed for treating certain cancers but the resistance developed by cancer cells to oxidative stress limits its potential use in clinics. To understand the mechanisms ...underlying resistance to oxidative stress, we found that the chronic exposure to an H
O
-generating system (ascorbate/menadione, Asc/Men) or catalase overexpression (CAT3 cells) increased the resistance of cancer cells to oxidative stress, likely by increasing the antioxidant status of cancer cells.
Modulation of catalase expression was performed by either protein overexpression or protein down-regulation using siRNA against catalase and aminotriazole as pharmacological inhibitor. The former approach was done by transfecting cells with a plasmid construct containing human catalase cDNA (CAT3 cells, derived from MCF-7 breast cancer cell line) or by generating resistant cells through chronic exposure to an oxidant injury (Resox cells). Cell survival was monitored by using the MTT reduction assay and further calculation of IC
values. Protein expression was done by Western blots procedures. The formation of reactive oxygen species was performed by flow cytometry. The transcriptional activity of human
promoter was assessed by using transfected cells with a plasmid containing the - 1518/+ 16 promoter domain.
Using Resox and CAT3 cells (derived from MCF-7 breast cancer cell line) as models for cancer resistance to pro-oxidative treatment, we found that arsenic trioxide (ATO) remarkably sensitized Resox and CAT3 cells to Asc/Men treatment. Since catalase is a key antioxidant enzyme involved in detoxifying Asc/Men (as shown by siRNA-mediated catalase knockdown) that is overexpressed in resistant cells, we hypothesized that ATO might regulate the expression levels of catalase. Consistently, catalase protein level is decreased in Resox cells when incubated with ATO likely by a decreased transcriptional activity of the
promoter.
Our findings support the proposal that ATO should be administered in combination with pro-oxidant drugs to enhance cancer cell death in solid tumors.
Integrin–extracellular matrix interactions play important roles in the coordinated integration of external and internal cues that are essential for proper development. To study the role of β1 ...integrin in the mammary gland, Itgβ1flox/flox mice were crossed with WAPiCre transgenic mice, which led to specific ablation of β1 integrin in luminal alveolar epithelial cells. In the β1 integrin mutant mammary gland, individual alveoli were disorganized resulting from alterations in cell–basement membrane associations. Activity of focal adhesion kinase (FAK) was also decreased in mutant mammary glands. Luminal cell proliferation was strongly inhibited in β1 integrin mutant glands, which correlated with a specific increase of p21Cip1 expression. In a p21Cip1 null background, there was a partial rescue of BrdU incorporation, providing in vivo evidence linking p21Cip1 to the proliferative defect observed in β1 integrin mutant glands. A connection between p21Cip1 and β1 integrin as well as FAK was also established in primary mammary cells. These results point to the essential role of β1 integrin signaling in mammary epithelial cell proliferation.
Heterogeneity in breast cancer Polyak, Kornelia
The Journal of clinical investigation,
10/2011, Letnik:
121, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Breast cancer is a heterogeneous disease. There is a high degree of diversity between and within tumors as well as among cancer-bearing individuals, and all of these factors together determine the ...risk of disease progression and therapeutic resistance. Advances in technologies such as whole-genome sequencing and functional viability screens now allow us to analyze tumors at unprecedented depths. However, translating this increasing knowledge into clinical practice remains a challenge in part due to tumor evolution driven by the diversity of cancer cell populations and their microenvironment. The articles in this Review series discuss recent advances in our understanding of breast tumor heterogeneity, therapies tailored based on this knowledge, and future ways of assessing and treating heterogeneous tumors.
Recently, great efforts have been made to use biosensors for the early diagnosis of cancer. Specifically, using a biomarker to detect H2O2 in physiological conditions is of great significance for ...understanding the signal transduction pathways and achieving early cancer diagnosis. In this work, we report an innovative H2O2 sensor that was fabricated by trimetallic AuPtPd nanocomposites platform on reduced graphene oxide (rGO) nanosheets with the modification of the rGO and trimetallic AuPtPd nanoparticles on a glassy carbon electrode (GCE) by physical adsorption. Transmission electron microscopy (TEM) and X-ray diffraction (XRD) were utilized to characterize and identify these unique nanocomposites. In addition, the electrochemical properties of the proposed sensor were evaluated by cyclic voltammetry and chronoamperometry. Electrochemical research has demonstrated that the AuPtPd/rGO-modified GCE showed excellent electrocatalytic activity towards the reduction of H2O2, including a wider linear range from 0.005 μM to 6.5 mM, a low detection limit of 2 nM, good selectivity and acceptable repeatability. Moreover, the sensor can monitor the release of H2O2 release from living cancer cells. Therefore, this study not only improves simplicity, sensitivity and quantitatively for detection H2O2 in cells at nM level but also provides a foundation for the biological and biomedical applications such as the early diagnosis of cancer.
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•A novel trimetallic AuPtPd nanocomposites decorated with reduced graphene oxide have been synthesized.•The sensor on the basis of proposed nanocomposites exhibited high performance to the detection of H2O2.•The sensor can be used to monitor the H2O2 release from living breast cancer cells.•The work was significant contribution to explain the signal transduction pathways and early diagnosis of cancer.
Apoptotic Potential of Glucomoringin Isothiocyanate Abd Karim, Nurul Ashikin; Adam, Aziza Hussein Bakheit; Jaafaru, Mohammed Sani ...
Molecules (Basel, Switzerland),
04/2023, Letnik:
28, Številka:
7
Journal Article
Recenzirano
Inhibition of several protein pathways involved in cancer cell regulation is a necessary key in the discovery of cancer chemotherapy. Moringa oleifera Lam is often used in traditional medicine for ...the treatment of various illnesses. The plant contains glucomoringin isothiocyanate (GMG-ITC) with therapeutic potential against various cancer cells. Therefore, GMG-ITC was evaluated for its cytotoxicity against the PC-3 prostate cancer cell line and its potential to induce apoptosis. GMG-ITC inhibited cell proliferation in the PC-3 cell line with IC50 value 3.5 µg/mL. Morphological changes as a result of GMG-ITC-induced apoptosis showed chromatin condensation, nuclear fragmentation, and membrane blebbing. Additionally, Annexin V assay showed proportion of cells in early and late apoptosis upon exposure to GMG-ITC in a time-dependent manner. Moreover, GMG-ITC induced a time-dependent G2/M phase arrest, with reduction of 39.1% in the PC-3 cell line. GMG-ITC also activates apoptotic genes including caspase, tumor suppressor gene (p53), Akt/MAPK, and Bax of the proapoptotic Bcl family. Early apoptosis proteins (JNK, Bad, Bcl2, and p53) were significantly upregulated upon GMG-ITC treatment. It is concluded that apoptosis induction was observed in PC-3 cells treated with GMG-ITC. These phenomena suggest that GMG-ITC from M. oleifera seeds could be useful as a future cytotoxic agent against prostate cancer.
Precision medicines exert selective pressure on tumour cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the ...evolving cancer. The PIK3CA-AKT-mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors (rapalogs) have caused responses in 'N-of-1' cases, and second-generation mTOR kinase inhibitors (TORKi) are currently in clinical trials. Here we sought to delineate the likely resistance mechanisms to existing mTOR inhibitors in human cell lines, as a guide for next-generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active-site mutation interfering with drug binding. Indeed, identical drug-resistant mutations have been also identified in drug-naive patients, suggesting that tumours with activating MTOR mutations will be intrinsically resistant to second-generation mTOR inhibitors. We report the development of a new class of mTOR inhibitors that overcomes resistance to existing first- and second-generation inhibitors. The third-generation mTOR inhibitor exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.
Patients treated with conventional cancer chemotherapy suffer from side effects of the drugs due to non-selective action of chemotherapeutic drugs to normal cells. Active targeting nanoparticles that ...are conjugated to targeting ligands on the surface of nanoparticles play an important role in improving drug selectivity to the cancer cell. Several chemotherapeutic drugs and traditional/herbal medicines reported for anticancer activities have been investigated for their selective delivery to cancer cells by active targeting nanoparticles. This systematic review summarizes reports on this application. Literature search was conducted through PubMed database search up to March 2017 using the terms nanoparticle, chemotherapy, traditional medicine, herbal medicine, natural medicine, natural compound, cancer treatment, and active targeting. Out of 695 published articles, 61 articles were included in the analysis based on the predefined inclusion and exclusion criteria. The targeting ligands included proteins/peptides, hyaluronic acid, folic acid, antibodies/antibody fragments, aptamer, and carbohydrates/polysaccharides. In vitro and in vivo studies suggest that active targeting nanoparticles increase selectivity in cellular uptake and/or cytotoxicity over the conventional chemotherapeutic drugs and non-targeted nanoparticle platform, particularly enhancement of drug efficacy and safety. However, clinical studies are required to confirm these findings.
Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) signaling is far more complex than initially anticipated and can lead to either anti- or protumorigenic effects, hampering the ...successful clinical use of therapeutic TRAIL receptor agonists. Cell autonomous resistance mechanisms have been identified in addition to paracrine factors that can modulate apoptosis sensitivity. The tumor microenvironment (TME), consisting of cellular and non-cellular components, is a source for multiple signals that are able to modulate TRAIL signaling in tumor and stromal cells. Particularly immune effector cells, also part of the TME, employ the TRAIL/TRAIL-R system whereby cell surface expressed TRAIL can activate apoptosis via TRAIL receptors on tumor cells, which is part of tumor immune surveillance. In this review we aim to dissect the impact of the TME on signaling induced by endogenous and exogenous/therapeutic TRAIL, thereby distinguishing different components of the TME such as immune effector cells, neutrophils, macrophages, and non-hematopoietic stromal cells. In addition, also non-cellular biochemical and biophysical properties of the TME are considered including mechanical stress, acidity, hypoxia, and glucose deprivation. Available literature thus far indicates that tumor-TME interactions are complex and often bidirectional leading to tumor-enhancing or tumor-reducing effects in a tumor model- and tumor type-dependent fashion. Multiple signals originating from different components of the TME simultaneously affect TRAIL receptor signaling. We conclude that in order to unleash the full clinical potential of TRAIL receptor agonists it will be necessary to increase our understanding of the contribution of different TME components on outcome of therapeutic TRAIL receptor activation in order to identify the most critical mechanism responsible for resistance, allowing the design of effective combination treatments.
MicroRNAs are small non-coding RNAs which play important roles in tumor progression. MiR-383-5p has been characterized as a cancer suppressor in several cancers. The aim of theses present study was ...to explore the role of miR-383-5p in the proliferation and chemosensitivity of ovarian cancer cells. MiR-383-5p expression was down-regulated while the expression of TRIM27 was up-regulated in ovarian cancer tissues and cell lines. We came up with the hypothesis that miR-383-5p might be involved in the tumor progression and chemoresistance of ovarian cancer through targeting TRIM27. Bioinformatics study and Luciferase reporter assay indicated that TRIM27 was a target of miR-383-5p and negatively regulated by miR-383-5p in ovarian cancer cells. Up-regulation of miR-383-5p was found to suppress cell proliferation and decrease Ki67 and PCNA expression in ovarian cancer cells (OVCAR3, A2780), suggesting that overexpressed miR-383-5p inhibited cell proliferation of ovarian cancer cells. In addition, up-regulation of miR-383-5p decreased the IC50 value of ovarian cancer cells to paclitaxel and increased cell apoptosis rate under the treatment of paclitaxel, indicating that overexpressed miR-383-5p enhanced chemosensitivity in ovarian cancer cells. However, overexpressed TRIM27 by pcDNA3.1-TRIM27 transfection counteracted the inhibitory effect of miR-383-5p on cell proliferation and chemoresistance in ovarian cancer cells. In vivo experiments also revealed that tumor growth could be inhibited by miR-383-5p mimic. Taken together, this present study found that miR-383-5p was lowly expressed while TRIM27 was highly expressed in ovarian cancer. Up-regulation of miR-383-5p inhibited cell proliferation, tumor growth and enhanced chemosensitivity of ovarian cancer cells through suppressing TRIM27 expression. Therefore, miR-383-5p/TRIM27 axis may be the potential target for the treatment of ovarian cancer.
Cancer is the second cause of death worldwide, surpassed only by cardiovascular diseases, due to the lack of early diagnosis, and high relapse rate after conventional therapies. Chemotherapy inhibits ...the rapid growth of cancer cells, but it also affects normal cells with fast proliferation rate. Therefore, it is imperative to develop other safe and more effective treatment strategies, such as gene therapy, in order to significantly improve the survival rate and life expectancy of patients with cancer. The aim of gene therapy is to transfect a therapeutic gene into the host cells to express itself and cause a beneficial biological effect. However, the efficacy of the proposed strategies has been insufficient for delivering the full potential of gene therapy in the clinic. The type of delivery vehicle (viral or non viral) chosen depends on the desired specificity of the gene therapy. The first gene therapy trials were performed with therapeutic genes driven by viral promoters such as the CMV promoter, which induces non-specific toxicity in normal cells and tissues, in addition to cancer cells. The use of tumor-specific promoters over-expressed in the tumor, induces specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several cancer- and/or tumor-specific promoters systems have been developed to target cancer cells. This review aims to provide up-to-date information concerning targeting gene therapy with cancer- and/or tumor-specific promoters including cancer suppressor genes, suicide genes, anti-tumor angiogenesis, gene silencing, and gene-editing technology, as well as the type of delivery vehicle employed. Gene therapy can be used to complement traditional therapies to provide more effective treatments.
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