One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Eldehna WM
PROVIDER: S-EPMC6009943 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Standardized treatment guidelines and effective drugs are not available for human triple-negative breast cancer (TNBC). Many efforts have recently been exerted to investigate the efficacy of natural compounds as anticancer agents owing to their low toxicity. However, no study has examined the effects of isobavachalcone (IBC) on the programmed cell death (PCD) of human triple-negative breast MDA-MB-231 cancer cells. In this study, IBC substantially inhibited the proliferation of MDA-MB-231 cells in concentration- and time-dependent manners. In addition, we found that IBC induced multiple cell death processes, such as apoptosis, necroptosis, and autophagy in MDA-MB-231 cells. The initial mechanism of IBC-mediated cell death in MDA-MB-231 cells involves the downregulation of Akt and p-Akt-473, an increase in the Bax/Bcl-2 ratio, and cleaved caspases-3 induced apoptosis; the upregulation of RIP3, p-RIP3 and MLKL induced necroptosis; as well as a simultaneous increase in LC3-II/I ratio induced autophagy. In addition, we observed that IBC induced mitochondrial dysfunction, thereby decreasing cellular ATP levels and increasing reactive oxygen species accumulation to induce PCD. These results suggest that IBC is a promising lead compound with anti-TNBC activity.
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Project description:Vasculogenic mimicry (VM) with the pattern of endothelial independent tubular structure formation lined by aggressive tumor cells mimics regular tumor blood vessels to ensure robust blood supply and correlates with the proliferation, invasion, metastasis, and poor prognosis of malignant tumors, which was demonstrated to be a major obstacle for resistance to antiangiogenesis therapy. Therefore, it is urgent to discover methods to abrogate the VM formation of tumors, which possesses important practical significance for improving tumor therapy. Brucine is a traditional medicinal herb extracted from seeds of Strychnos nux-vomica L. (Loganiaceae) exhibiting antitumor activity in a variety of cancer models. In the present study, the effect of brucine on vasculogenic mimicry and the related mechanism are to be investigated. We demonstrated that, in a triple-negative breast cancer cell line MDA-MB-231, brucine induced a dose-dependent inhibitory effect on cell proliferation along with apoptosis induction at higher concentrations. The further study showed that brucine inhibited cell migration and invasion with a dose-dependent manner. Our results for the first time indicated that brucine could disrupt F-actin cytoskeleton and microtubule structure, thereby impairing hallmarks of aggressive tumors, like migration, invasion, and holding a possibility of suppressing vasculogenic mimicry. Hence, the inhibitory effect of brucine on vasculogenic mimicry was further verified. The results illustrated that brucine significantly suppressed vasculogenic mimicry tube formation with a dose-dependent effect indicated by the change of the number of tubules, intersections, and mean length of tubules. The in-depth molecular mechanism of vasculogenic mimicry suppression induced by brucine was finally suggested. It was demonstrated that brucine inhibited vasculogenic mimicry which might be through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2 and matrix metalloproteinase-2 and metalloproteinase-9.
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Project description:Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and metastatic potential as well as Epithelial-Mesenchymal Transition (EMT) and stemness features. In the last few years, our research focused on the function of MCL1, an antiapoptotic protein frequently deregulated in TNBC. Here, we demonstrate that MCL1 inhibition by A-1210477, a specific BH3-mimetic, promotes anoikis/apoptosis in the MDA-MB-231 cell line, as shown via an increase in proapoptotic markers and caspase activation. Our evidence also shows A-1210477 effects on Focal Adhesions (FAs) impairing the integrin trim and survival signaling pathways, such as FAK, AKT, ERK, NF-κB, and GSK3β-inducing anoikis, thus suggesting a putative role of MCL1 in regulation of FA dynamics. Interestingly, in accordance with these results, we observed a reduction in migratory and invasiveness capabilities as confirmed by a decrease in metalloproteinases (MMPs) levels following A-1210477 treatment. Moreover, MCL1 inhibition promotes a reduction in EMT characteristics as demonstrated by the downregulation of Vimentin, MUC1, DNMT1, and a surprising re-expression of E-Cadherin, suggesting a possible mesenchymal-like phenotype reversion. In addition, we also observed the downregulation of stemness makers such as OCT3/4, SOX2, NANOG, as well as CD133, EpCAM, and CD49f. Our findings support the idea that MCL1 inhibition in MDA-MB-231 could be crucial to reduce anoikis resistance, aggressiveness, and metastatic potential and to minimize EMT and stemness features that distinguish TNBC.
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Project description:Phosphate ions are the most abundant anions inside the cells, and they are increasingly gaining attention as key modulators of cellular function and gene expression. However, little is known about the effect of inorganic phosphate ions on cancer cells, particularly breast cancer cells. Here, we investigated the toxicity of different phosphate compounds to triple-negative human breast cancer cells, particularly, MDA-MB-231, and compared it to that of human monocytes, THP-1. We found that, unlike dihydrogen phosphate (H2PO4-), hydrogen phosphate (HPO42-) at 20 mM or lower concentrations induced breast cancer cell death more than immune cell death, mainly via apoptosis. We correlate this effect to the fact that phosphate in the form of HPO42- raises pH levels to alkaline levels which are not optimum for transport of phosphate into cancer cells. The results in this study highlight the importance of further exploring hydrogen phosphate (HPO42-) as a potential therapeutic for the treatment of breast cancer.
| S-EPMC8964734 | biostudies-literature
Project description:Recent studies demonstrate that interstitial inorganic phosphate is significantly elevated in the breast cancer microenvironment as compared to normal tissue. In addition it has been shown that breast cancer cells express high levels of the NaPi-IIb carrier (SLC34A2), suggesting that this carrier may play a role in breast cancer progression. However, the biochemical behavior of inorganic phosphate (Pi) transporter in this cancer type remains elusive.In this work, we characterize the kinetic parameters of Pi transport in the aggressive human breast cancer cell line, MDA-MB-231, and correlated Pi transport with cell migration and adhesion.We determined the influence of sodium concentration, pH, metabolic inhibitors, as well as the affinity for inorganic phosphate in Pi transport. We observed that the inorganic phosphate is dependent on sodium transport (K0,5 value = 21.98 mM for NaCl). Furthermore, the transport is modulated by different pH values and increasing concentrations of Pi, following the Michaelis-Menten kinetics (K0,5 = 0.08 mM Pi). PFA, monensin, furosemide and ouabain inhibited Pi transport, cell migration and adhesion.Taken together, these results showed that the uptake of Pi in MDA-MB-231 cells is modulated by sodium and by regulatory mechanisms of intracellular sodium gradient. General Significance: Pi transport might be regarded as a potential target for therapy against tumor progression.
| S-EPMC5802448 | biostudies-literature
Project description:Triple negative breast cancer (TNBC), ~ 10-20% of diagnosed breast cancers, metastasizes to brain, lungs, liver. Iodine nanoparticle (INP) radioenhancers specifically localize to human TNBC MDA-MB-231 tumors growing in mouse brains after iv injection, significantly extending survival of mice after radiation therapy (RT). A prominent rim of INP contrast (MicroCT) previously seen in subcutaneous tumors but not intracerebral gliomas, provide calculated X-ray dose-enhancements up to > eightfold. Here, MDA-MB-231-cells, INPs, CD31 were examined by fluorescence confocal microscopy. Most INP staining co-localized with CD31 in the tumor center and periphery. Greatest INP/CD31 staining was in the tumor periphery, the region of increased MicroCT contrast. Tumor cells are seen to line irregularly-shaped spaces (ISS) with INP, CD31 staining very close to or on the tumor cell surface and PAS stain on their boundary and may represent a unique form of CD31-expressing vascular mimicry in intracerebral 231-tumors. INP/CD31 co-staining is also seen around ISS formed around tumor cells migrating on CD31+ blood-vessels. The significant radiation dose enhancement to the prolific collagen I containing, INP-binding ISS found throughout the tumor but concentrated in the tumor rim, may contribute significantly to the life extensions observed after INP-RT; VM could represent a new drug/NP, particularly INP, tumor-homing target.
| S-EPMC7806637 | biostudies-literature
Project description:We have previously identified a novel Aurora-A-mediated Serine 379 (S379) phosphorylation of a poly(C)-binding protein, hnRNPK, the overexpression of which is frequently observed in various cancers. It is known that the oncogenic Aurora-A kinase promotes the malignancy of cancer cells. This study aims to investigate the unexplored functions of hnRNPK S379 phosphorylation using MDA-MB-231 cells, a triple negative breast cancer cell that has amplification of the Aurora-A kinase gene. Accordingly, we established two cell lines in which the endogenous hnRNPK was replaced with either S379D or S379A hnRNPK respectively. Notably, we found that a phosphorylation-mimic S379D mutant of hnRNPK suppressed cell migration and, conversely, a phosphorylation-defective S379A mutant promoted migration. Moreover, Twist was downregulated upon hnRNPK S379 phosphorylation, whereas β-catenin and MMP12 were increased when there was loss of hnRNPK S379 phosphorylation in MDA-MB-231 cells. Furthermore, S379A hnRNPK increases stability of β-catenin in MDA-MB-231 cells. In conclusion, our results suggest that hnRNPK S379 phosphorylation regulates migration via the EMT signaling pathway.
| S-EPMC6527834 | biostudies-other
Project description:Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Because TNBC lacks the expression of commonly targeted receptors, it is challenging to develop a new imaging agent for this cancer subtype. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-protein complexes that have been linked to tumor development and progression. Considering the high expression of hnRNPA2B1, an hnRNP subtype, in TNBC MDA-MB-231 cells, this study aimed to develop a novel hnRNPA2B1 antibody-based nuclear imaging agent. The hnRNPA2B1-specific antibody was radiolabeled with 64Cu and evaluated in vitro and in vivo. The trans-cyclooctene (TCO) was functionalized on the antibody to obtain hnRNP-PEG4-TCO and reactive tetrazine (Tz) on the ultrastable bifunctional chelator PCB-TE2A-alkyne to yield PCB-TE2A-Tz for the inverse electron demand Diels-Alder reaction. The 64Cu-radiolabeled antibody was administered and imaged at 1-18 h time points for conventional imaging. Alternatively, the unlabeled antibody conjugate was administered, and 48 h later radiolabeled 64Cu-PCB-TE2A-Tz was administered to the same mice for the pretargeting strategy and imaged at the same time intervals for direct comparison. The tumor was successfully visualized in both strategies, and comparatively, pretargeting showed superior results. The 64Cu-PCB-TE2A-Tz was successfully clicked at the tumor site with hnRNP-PEG4-TCO and the non-clicked were concurrently eliminated. This led to increase the tumor uptake with extremely high tumor-to-background ratio manifested by positron emission tomography (PET) imaging and biodistribution studies.
| S-EPMC9415040 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is associated with unfavorable prognosis and high relapse rates following chemotherapy. There is an urgent need to develop effective targeted therapy for this BC subtype. The type I insulin-like growth factor receptor (IGF-IR) was identified as a potential target for BC management. We previously reported on the production of the IGF-Trap, a soluble IGF-1R fusion protein that reduces the bioavailability of circulating IGF-1 and IGF-2 to the cognate receptor, impeding signaling. In nude mice xenotransplanted with the human TNBC MDA-MB-231 cells, we found variable responses to this inhibitor. We used this model to investigate potential resistance mechanisms to IGF-targeted therapy. We show here that prolonged exposure of MDA-MB-231 cells to the IGF-Trap in vitro selected a resistant subpopulation that proliferated unhindered in the presence of the IGF-Trap. We identified in these cells increased fibroblast growth factor receptor 1 (FGFR1) activation levels that sensitized them to the FGFR1-specific tyrosine kinase inhibitor PD166866. Treatment with this inhibitor caused cell cycle arrest in both the parental and resistant cells, markedly increasing cell death in the latter. When combined with the IGF-Trap, an increase in cell cycle arrest was observed in the resistant cells. Moreover, FGFR1 silencing increased the sensitivity of these cells to IGF-Trap treatment in vivo. Our data identify increased FGFR1 signaling as a resistance mechanism to targeted inhibition of the IGF-IR and suggest that dual IGF-1R/FGFR1 blockade may be required to overcome TNBC cell resistance to IGF-axis inhibitors.
| S-EPMC8065809 | biostudies-literature
Project description:This work compared the metabolic profile of a parental MDA-MB-231 cisplatin-sensitive triple negative breast cancer (TNBC) cell line with that of a derived cisplatin-resistant line, to characterize inherent metabolic adaptations to resistance, as a means for marker and new TNBC therapies discovery. Supported by cytotoxic, microscopic and biochemical characterization of both lines, Nuclear Magnetic Resonance (NMR) metabolomics was employed to characterize cell polar extracts for the two cell lines, as a function of time (0, 24 and 48 h), and identify statistically relevant differences both between sensitive and resistant cells and their time course behavior. Biochemical results revealed a slight increase in activation of the NF-κB pathway and a marked decrease of the ERK signaling pathway in resistant cells. This was accompanied by lower glycolytic and glutaminolytic activities, possibly linked to glutamine being required to increase stemness capacity and, hence, higher survival to cisplatin. The TCA cycle dynamics seemed to be time-dependent, with an apparent activation at 48 h preferentially supported by anaplerotic aromatic amino acids, leucine and lysine. A distinct behavior of leucine, compared to the other branched-chain-amino-acids, suggested the importance of the recognized relationship between leucine and in mTOR-mediated autophagy to increase resistance. Suggested markers of MDA-MB-231 TNBC cisplatin-resistance included higher phosphocreatine/creatine ratios, hypotaurine/taurine-mediated antioxidant protective mechanisms, a generalized marked depletion in nucleotides/nucleosides, and a distinctive pattern of choline compounds. Although the putative hypotheses generated here require biological demonstration, they pave the way to the use of metabolites as markers of cisplatin-resistance in TNBC and as guidance to develop therapies.
| S-EPMC10699005 | biostudies-literature