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Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a transcriptional factor which acts as a regulator for cellular oxidative stress, and tightly regulated by Kelch‐like ECH‐associated protein 1 (Keap1). In this study, we found that auranofin and paclitaxel combination treatment increased TUNEL positive apoptotic cells and enhanced the DNA damage marker γ‐H2AX in MCF‐7 and MDA‐MB‐231 breast cancer cells. The immunoblotting analysis revealed the combination of auranofin and paclitaxel significantly increased the FOXO3 expression in a concentration dependent manner. Further we observed that auranofin and paclitaxel treatment prevents the translocation of Nrf2 in a concentration dependent manner. The increased FOXO3 expression might be involved in the cytoplasmic degradation of Nrf1‐Keap1 complex. Further, the molecular docking results confirm auranofin act as the agonist for Foxo3. Therefore, the present results suggest that auranofin sensitize the breast cancer cells to paclitaxel via regulating FOXO3/Nrf2/Keap1signaling pathway. Significance Statement: The present results show that auranofin enhances paclitaxel induced TUNEL positive apoptotic cells. Further, auranofin treatment increases FOXO3 which in turn inhibit the dissociation of Nrf2 and Keap1 in both MDA‐MB‐231 and MCF‐7 cell lines. Therefore, the present results clearly illustrate the chemosensitizing property of auranofin via regulating FOXO3/Nrf2/Keap1 signaling pathway in the breast cancer cells. Auranofin is already a Food and Drug administration approved drug and it could be considered for the clinical applications after preclinical experimentation. [ABSTRACT FROM AUTHOR]

The intrinsic redox status of cancer cells limits the efficacy of chemotherapeutic drugs. Auranofin, a Food and Drug Administration‐approved gold‐containing compound, documented with effective pharmacokinetics and safety profiles in humans, has recently been repurposed for anticancer activity. This study examined the paclitaxel‐sensitizing effect of auranofin by targeting redox balance in the MDA‐MB‐231 and MCF‐7 breast cancer cell lines. Auranofin treatment depletes the activities of superoxide dismutase, catalase, and glutathione peroxidase and alters the redox ratio in the breast cancer cell lines. Furthermore, it has been noticed that auranofin augmented paclitaxel‐mediated cytotoxicity in a concentration‐dependent manner in both MDA‐MB‐231 and MCF‐7 cell lines. Moreover, auranofin increased the levels of intracellular reactive oxygen species (observed using 2, 7‐diacetyl dichlorofluorescein diacetate staining) and subsequently altered the mitochondrial membrane potential (rhodamine‐123 staining) in a concentration‐dependent manner. Further, the expression of apoptotic marker p21 was found to be higher in auranofin plus paclitaxel‐treated breast cancer cells compared to paclitaxel‐alone treatment. Thus, the present results illustrate the chemosensitizing property of auranofin in MDA‐MB‐231 and MCF‐7 breast cancer cell lines via oxidative metabolism. Therefore, auranofin could be considered a chemosensitizing agent during cancer chemotherapy. Significance statement: In this study, auranofin, a Food and Drug Administration‐approved drug, has been repurposed for anticancer activity. The results illustrate that auranofin improved paclitaxel‐mediated cytotoxicity in breast cancer cell lines. The auranofin treatment altered the intracellular redox balance in the breast cancer cells, which contributes to paclitaxel‐mediated cell cycle arrest and subsequent apoptotic cell death. Thus, the present results illustrate the chemosensitizing property of auranofin in breast cancer cell lines via oxidative metabolism. Therefore, auranofin could be considered a chemosensitizing agent during cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Synthesis of β -CDP/QD NCs using epichlorohydrin linker to overcome. P-glycoprotein (P-gp) mediated MDR in cancer cells. The β -CDP/QD NCs enter the MDR cancer cells through endocytosis. The QCT released from the nanocarrier enhances the intracellular availability of DOX via blocking the drug efflux function of P-gp. [Display omitted] • The β -CDP/QD NCs were successfully synthesized by the freeze-dried method. • Spectroscopic and microscopic studies evaluate the encapsulation of drugs in polymer. • The β -CDP/QD NCs show burst and sustained release of quercetin and doxorubicin. • β -CDP/QD NCs show enhanced apoptotic cell death in MDR cancer cells. In this study, we prepared a β -cyclodextrin polymer (β -CDP) co-loaded quercetin (QCT) and doxorubicin (DOX) nanocarrier (β -CDP/QD NCs) by freeze-dried method to combat P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in KB-ChR 8–5 cancer cells. Various microscopic and spectroscopic techniques were employed to characterize the prepared nanocarrier. The molecular docking studies confirm the effective binding interactions of QCT and DOX with the synthesized β -CD polymer. The in vitro drug release study illustrates the sustainable release of DOX and QCT from the β -CDP nanocarrier. Further, we noticed that the QCT released from the β -CDP nanocarrier improved the intracellular availability of DOX via modulating P-gp drug efflux function in KB-ChR 8–5 cells and MCF-7/DOX cancer cells. Cell uptake results confirmed the successful internalization of DOX in KB-ChR 8–5 cells compared with free DOX. Cell-based assays such as nuclear condensation, alteration in the mitochondrial membrane potential (MMP), and apoptosis morphological changes confirmed the enhanced anticancer effect of β -CDP/QD NCs in the resistant cancer cells. Hence, QCT and DOX co-loaded β -CDP may be considered effective in achieving maximum cell death in the P-gp overexpressing MDR cancer cells. [ABSTRACT FROM AUTHOR]

Studies were performed to examine the affect of nitric oxide (NO) on expression of the divalent metal transporter (DMT1) in undifferentiated P19 embryonic carcinoma cells. DMT1 has four known isoforms which differ in both the N- and C-terminals. Results demonstrate that exposure of P19 cells to the NO precursor, sodium nitro-prusside (SNP), resulted in a decrease in expression of both positive (+) and negative (–) IRE isoforms of DMT1 with no change in the 1A species. Regulation was not as a result of decreased stability of message but was caused by reduction in transcription of the DMT1 1B isoforms. Similar results were observed in other cell lines, including PC12 and SH-SY5Y cells and rat primary sympathetic neurons. Nuclear NF-κB was decreased after SNP treatment, suggesting that NF-κB may mediate this response. Luciferase reporter assays with normal and NF-κB mutated constructs of the 1B promoter confirm that the NF-κB site between −23 to −19 upstream from the transcription start site was responsible for regulating expression. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays further demonstrate that the p65 subunit of NF-κB and not p50 binding is specifically decreased by NO treatment. Results of these studies provide a general mechanism responsible for regulating DMT1 expression induced by stress-related signaling processes in vivo. [ABSTRACT FROM AUTHOR]

Garlic is a vegetable with numerous pro-health properties, showing high antioxidant capacity, and cytotoxicity for various malignant cells. The inhibition of cell proliferation by garlic is mainly attributed to the organosulfur compounds (OSCs), but it is far from obvious which constituents of garlic indeed participate in the antioxidant and cytotoxic action of garlic extracts. This study aimed to obtain insight into this question by examining the antioxidant activity and cytotoxicity of six OSCs and five phenolics present in garlic. Three common assays of antioxidant activity were employed (ABTS● decolorization, DPPH● decolorization, and FRAP). Cytotoxicity of both classes of compounds to PEO1 and SKOV-3 ovarian cancer cells, and MRC-5 fibroblasts was compared. Negligible antioxidant activities of the studied OSCs (alliin, allicin, S-allyl-D-cysteine, allyl sulfide, diallyl disulfide, and diallyl trisulfide) were observed, excluding the possibility of any significant contribution of these compounds to the total antioxidant capacity (TAC) of garlic extracts estimated by the commonly used reductive assays. Comparable cytotoxic activities of OSCs and phenolics (caffeic, p-coumaric, ferulic, gallic acids, and quercetin) indicate that both classes of compounds may contribute to the cytotoxic action of garlic. [ABSTRACT FROM AUTHOR]

Ferulic acid (FA) is a common phenolic acid in plants and is known to effectively combat cancer; however, the precise mechanism is still unknown. In this study, we examined the effect of FA on breast cancer (BC) cells, together with its molecular mechanism. We observed that FA greatly decreased BC cell viability without any obvious inhibitory effects on normal cell viability. Further, FA could significantly lead to the apoptosis of MDA‐MB‐231 cells. FA administration dramatically increased the levels of reactive oxygen species (ROS) in MDA‐MB‐231 cells, and mitochondria‐dependent apoptosis occurred via the MAPK/STAT3/NF‐κB pathways. It was also demonstrated that with an increase in FA treatment time, the G2/M phase ratio increased and the expression of p‐AKT and cycle‐related proteins was inhibited. The migration of MDA‐MB‐231 cells was significantly inhibited after FA treatment. FA reduced N‐cadherin, vimentin, and SNAI 1 expression levels through the MAPK signaling pathway. Pretreatment with N‐acetylcysteine and MAPK inhibitors (SP600125 or SB203580) increased the expression of these proteins, whereas pretreatment with the MAPK inhibitor (FR180204) decreased their expression. In conclusion, FA can increase ROS levels, induce mitochondria‐dependent apoptosis, block the G2/M phase cycle, and inhibit cell migration. Thus, FA may be a promising new medication in the treatment of BC. [ABSTRACT FROM AUTHOR]

To explore whether the p17 protein of oncolytic avian reovirus (ARV) mediates cell migration and invadopodia formation, we applied several molecular biological approaches for studying the involved cellular factors and signal pathways. We found that ARV p17 activates the p53/phosphatase and tensin homolog (PTEN) pathway to suppress the focal adhesion kinase (FAK)/Src signaling and downstream signal molecules, thus inhibiting cell migration and the formation of invadopodia in murine melanoma cancer cell line (B16-F10). Importantly, p17-induced formation of invadopodia could be reversed in cells transfected with the mutant PTENC124A. p17 protein was found to significantly reduce the expression levels of tyrosine kinase substrate 5 (TKs5), Rab40b, non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), and matrix metalloproteinases (MMP9), suggesting that TKs5 and Rab40b were transcriptionally downregulated by p17. Furthermore, we found that p17 suppresses the formation of the TKs5/NCK1 complex. Coexpression of TKs5 and Rab40b in B16-F10 cancer cells reversed p17-modulated suppression of the formation of invadopodia. This work provides new insights into p17-modulated suppression of invadopodia formation by activating the p53/PTEN pathway, suppressing the FAK/Src pathway, and inhibiting the formation of the TKs5/NCK1 complex. [ABSTRACT FROM AUTHOR]

The phenolic compounds of four Palestinian honey samples (PH1-PH4) and their antibacterial effects as well as their cytotoxic, cytostatic, and antimigration effects in human breast cancer cell line (MDA) were evaluated here. HPLC analysis of PH2 (Cornflower), PH3 (Milk thistle), and PH4 (Ziziphus) revealed 15 phenolic compounds, namely, caffeic acid, carvacrol, chrysin, ellagic acid, galangin, gallic acid, kaempferol, p-coumaric acid, pinobanksin, pinocembrin, protocatechuic acid, quercetin, rutin, salicylic acid, and silydamin. The minimum inhibitory concentration (MIC) method applied to Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), and Escherichia coli (E. coli). A strong positive correlation was detected between antimicrobial activity (E. coli) and p-coumaric acid, quercetin, and silydamin. IC50 values for DPPH neutralization varied from 0.19 w/w% to 10 w/w%. The potential anticancer properties of the honey samples were evaluated on MDA cells. Samples PH2 and PH3 demonstrated cytostatic activity, reducing cell viability by about 43% at non-toxic concentration of 4 mg/mL. The cytostatic effects were strongly correlated with the presence of caffeic acid, chrysin, protocatechuic acid, rutin, and salicylic acid (p < 0.01). Moreover, the cell migration rate was significantly reduced (by up to 85%) with PH2 and PH3 compared to untreated cells (p < 0.05). A strong positive correlation was observed between the cytostatic effects of the concentration of carvacrol and Pinocembrin (p < 0.01). Our findings validate honey’s antibacterial properties and suggest its anticancer benefits may stem from cytostatic and antimigration effects. [ABSTRACT FROM AUTHOR]

Both the senescence of cancer cells and the maintenance of cancer stem cells seem to be mutually exclusive because senescence is considered a physiological mechanism that effectively suppresses tumor growth. Recent studies have revealed common signaling pathways between cellular senescence and the maintenance of stemness in cancer cells, thus challenging the conventional understanding of this process. Although the links between these processes have not yet been fully elucidated, emerging evidence indicates that senescent cancer cells can undergo reprograming to recover stemness. Herein, we provide a comprehensive overview of the close correlation between senescence and stemness reprograming in cancer cells, with a particular focus on the mechanisms by which senescent cancer cells recover their stemness in various tumor systems. [ABSTRACT FROM AUTHOR]

Many proteins lack stable 3D structures. These intrinsically disordered proteins (IDPs) or hybrid proteins containing ordered domains with intrinsically disordered protein regions (IDPRs) often carry out regulatory functions related to molecular recognition and signal transduction. IDPs/IDPRs constitute a substantial portion of the human proteome and are termed "the unfoldome". Herein, we probe the human breast cancer unfoldome and investigate relations between IDPs and key disease genes and pathways. We utilized bottom-up proteomics, MudPIT (Multidimensional Protein Identification Technology), to profile differentially expressed IDPs in human normal (MCF-10A) and breast cancer (BT-549) cell lines. Overall, we identified 2271 protein groups in the unfoldome of normal and cancer proteomes, with 148 IDPs found to be significantly differentially expressed in cancer cells. Further analysis produced annotations of 140 IDPs, which were then classified to GO (Gene Ontology) categories and pathways. In total, 65% (91 of 140) IDPs were related to various diseases, and 20% (28 of 140) mapped to cancer terms. A substantial portion of the differentially expressed IDPs contained disordered regions, confirmed by in silico characterization. Overall, our analyses suggest high levels of interactivity in the human cancer unfoldome and a prevalence of moderately and highly disordered proteins in the network. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most common male cancer. Its incidence derives from the interaction between modifiable and non-modifiable factors. The progression of prostate cancer into a more aggressive phenotype is associated with chronic inflammation and increased ROS production. For their biological properties, some phytochemicals from fruits and vegetable emerge as a promise strategy for cancer progression delay. These bioactive compounds are found in the highest amounts in peels and seeds. Poncirus trifoliata (L.) Raf. (PT) has been widely used in traditional medicine and retains anti-inflammatory, anti-bacterial, and anticancer effects. The seeds of P. trifoliata were exhaustively extracted by maceration with methanol as the solvent. The cell proliferation rate was performed by MTT and flow cytometry, while the apoptosis signals were analyzed by Western blotting and TUNEL assay. P. trifoliata seed extract reduced LNCaP and PC3 cell viability and induced cell cycle arrest at the G0/G1phase and apoptosis. In addition, a reduction in the AKT/mTOR pathway has been observed together with the up-regulation of stress-activated MAPK (p38 and c-Jun N-terminal kinase). Based on the study, the anti-growth effects of PT seed extract on prostate tumor cells give indications on the potential of the phytochemical drug for the treatment of this type of cancer. However, future in-depth studies are necessary to identify which components are mainly responsible for the anti-neoplastic response. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (AuNPs) are very valuable materials used in many fields, especially in biomedical applications. In this study Rheum ribes Lam-derived AuNPs (Rrib*AuNPs) were synthesized in an environmentally friendly, easy and low-cost method using the extract obtained from the waste skin of the fruit known as Rheum ribes Lam (Kurdish banana). Functional groups of phytochemicals responsible for redox reactions were determined by FTIR data. Properties of synthesized Rrib*AuNPs UV-vis, TEM, FE-SEM, Zeta potential, XRD, AFM, TGA-DTA), EDX), Zetasizer devices. In the characterization data, it was determined that Rrib*AuNPs had an average size distribution of 58.27 nm, a spherical appearance morphology, a maximum absorbance of 543.96 nm, a surface charge of −23.0 mV, a monodisperse and stable structure. It was determined by microdilution that the synthesized Rrib*AuNPs had antibacterial and anti-fungal effects with 0.03–0.50 µg ml−1 Minimum Inhibition Concentration amounts. The cytotoxic effects of Rrib*AuNPs on cancer and healthy cell lines were investigated using the MTT method. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is the most prevalent type of kidney cancer originating from renal tubular epithelial cells, with clear cell RCC comprising approximately 80% of cases. The primary treatment modalities for RCC are surgery and targeted therapy, albeit with suboptimal efficacies. Despite progress in RCC research, significant challenges persist, including advanced distant metastasis, delayed diagnosis, and drug resistance. Growing evidence suggests that extracellular vesicles (EVs) play a pivotal role in multiple aspects of RCC, including tumorigenesis, metastasis, immune evasion, and drug response. These membrane-bound vesicles are released into the extracellular environment by nearly all cell types and are capable of transferring various bioactive molecules, including RNA, DNA, proteins, and lipids, aiding intercellular communication. The molecular cargo carried by EVs renders them an attractive resource for biomarker identification, while their multifarious role in the RCC offers opportunities for diagnosis and targeted interventions, including EV-based therapies. As the most versatile type of EVs, exosomes have attracted much attention as nanocarriers of biologicals, with multi-range signaling effects. Despite the growing interest in exosomes, there is currently no widely accepted consensus on their subtypes and properties. The emerging heterogeneity of exosomes presents both methodological challenges and exciting opportunities for diagnostic and clinical interventions. This article reviews the characteristics and functions of exosomes, with a particular reference to the recent advances in their application to the diagnosis and treatment of RCC. [ABSTRACT FROM AUTHOR]

The issue of toxicity associated with existing cancer drugs necessitates the exploration of the anticancer potentials of natural products such as caffeic acid (CA). Here, we determined the effect of CA on the proliferation, migration, and stem cell-like properties of DU-145 prostate cancer cells. Tetrazolium-based colorimetric assay and flow cytometric analysis showed that CA decreased cell proliferation in a dose- and time-dependent manner without affecting cell cycle progression. CA also inhibited cell migration and repressed epithelial-to-mesenchymal transition by upregulating the expression of cadherin 1 (CDH1) and downregulating the expression of cadherin 2 (CDH2). Furthermore, CA reduced the cancer stem cell population from 95% to 63% and 47% at concentrations of 1.25 and 2.5 mg/mL, respectively; and inhibited stem cell-like properties by downregulating the expression of NANOG and octamer-binding transcription factor 4 (OCT4) genes. These findings suggest that CA could be considered in the development of improved chemotherapy against prostate cancer. [ABSTRACT FROM AUTHOR]

Efficient delivery of functional factors into target cells remains challenging. Although extracellular vesicles (EVs) are considered to be potential therapeutic delivery vehicles, a variety of efficient therapeutic delivery tools are still needed for cancer cells. Herein, we demonstrated a promising method to deliver EVs to refractory cancer cells via a small molecule-induced trafficking system. We generated an inducible interaction system between the FKBP12-rapamycin-binding protein (FRB) domain and FK506 binding protein (FKBP) to deliver specific cargo to EVs. CD9, an abundant protein in EVs, was fused to the FRB domain, and the specific cargo to be delivered was linked to FKBP. Rapamycin recruited validated cargo to EVs through protein-protein interactions (PPIs), such as the FKBP-FRB interaction system. The released EVs were functionally delivered to refractory cancer cells, triple negative breast cancer cells, non-small cell lung cancer cells, and pancreatic cancer cells. Therefore, the functional delivery system driven by reversible PPIs may provide new possibilities for a therapeutic cure against refractory cancers. [ABSTRACT FROM AUTHOR]

The main reasons for the limited clinical efficacy of the platinum(II)-based agent cisplatin include drug resistance and significant side effects. Due to their better stability, as well as the possibility to introduce biologically active ligands in their axial positions constructing multifunctional prodrugs, creating platinum(IV) complexes is a tempting strategy for addressing these limitations. Another strategy for developing chemotherapeutics with lower toxicity relies on the ability of nanoparticles to accumulate in greater quantities in tumor tissues through passive targeting. To combine the two approaches, three platinum(IV) conjugates based on a cisplatin scaffold containing in the axial positions derivatives of caffeic and ferulic acid were prepared and loaded into SBA-15 to produce the corresponding mesoporous silica nanoparticles (MSNs). The free platinum(IV) conjugates demonstrated higher or comparable activity with respect to cisplatin against different human breast cancer cell lines, while upon immobilization, superior antiproliferative activity with markedly increased cytotoxicity (more than 1000-fold lower IC50 values) compared to cisplatin was observed. Mechanistic investigations with the most potent conjugate, cisplatin-diacetyl caffeate (1), and the corresponding MSNs (SBA-15|1) in a 4T1 mouse breast cancer cell line showed that these compounds induce apoptotic cell death causing strong caspase activation. In vivo, in BALB/c mice, 1 and SBA-15|1 inhibited the tumor growth while decreasing the necrotic area and lowering the mitotic rate. [ABSTRACT FROM AUTHOR]

Cancer is a horrific disease that, to date, has no cure. It is caused by various factors and takes many lives. Apoptosis is a programmed cell death mechanism and if it does not function correctly in cancer cells, it can lead to severe disease. There are various signaling pathways for regulating apoptosis in cancer cells. Flavonoids are non-artificial natural bioactive compounds that are gaining attention as being capable of for inducing apoptosis in cancer cells. Among these, in this study, we focus on flavones. Flavones are a subclass of the numerous available flavonoids and possess several bioactive functions. Some of the most reported and well-known critical flavones, namely apigenin, acacetin, baicalein, luteolin, tangeretin, and wogonin, are discussed in depth in this review. Our main aim is to investigate the effects of the selected flavones on apoptosis and cell signaling pathways that contribute to death due to various types of cancers. [ABSTRACT FROM AUTHOR]

Expression of the cellular transmembrane receptor αvβ6 integrin is mostly restricted to malignant epithelial cells in a wide variety of carcinomas, including pancreatic and others derived from epithelial tissues. Thus, this protein is considered an attractive target for tumour imaging and therapy. Two different 68Ga hexadentate tris (3,4-hydroxypyridinone) (THP) chelators were produced in this study and coupled to the αvβ6 integrin–selective peptide cyclo(FRGDLAFp(NMe)K) via NHS chemistry. Radiolabelling experiments confirmed a high radiochemical yield of the two PET probes. In addition, cellular binding studies showed high binding affinities in the nanomolar range. The two integrin αvβ6-peptide-THP synthesized and radiolabeled in this study will facilitate in vivo monitoring of transmembrane receptor αvβ6 integrin by using the advantage of THP chemistry for rapid, efficient and stable gallium chelation. [ABSTRACT FROM AUTHOR]

Posaconazole (POS) has been reported to present potential antitumor activity for glioblastoma (GBM). However, its molecular mechanisms remain unclear. In this study, we found that POS has potent cytotoxicity and inhibits cell viability and proliferation in GBM. In addition, we adopted a sphere formation assay to detect the self-renewal capacity, performed western blotting to measure cancer stem-like cells (CSCs) marker proteins (CD133, SOX2, Nanog and Oct4) and applied flow cytometry to monitor the subpopulation of CD144+/CD33+ cells, and the results all demonstrated that POS can remarkably weaken CSCs stemness. Furthermore, western blotting, immunoflurescence, transmission electron microscopy and acridine orange staining were performed to detect autophagy-related proteins (LC3, SQSTM1, Beclin 1 and Atg5), count the numbers of endogenous LC3 puncta, visually observe the ultrastructural morphology of autophagosomes and judge the formation of acidic vesicular organelles, respectively, and the results validated that POS promotes autophagy induction. Importantly, the suppressive effect of POS on CSCs stemness was partially relieved when autophagy was blocked by the autophagy inhibitor chloroquine (CQ) or Atg5 shRNA. Bioinformatic techniques, including weighted gene coexpression network analysis (WGCNA), gene set difference analysis (GSVA) and KEGG pathway analysis, combined with experimental validations showed that survivin, which is implicated in both autophagy and the stem cell index, is one of the target proteins of POS and that POS weakens CSCs stemness via suppressing the Wnt/ß-catenin signaling pathway in GBM. Besides, POS-induced autophagy and the Wnt/ß-catenin signaling pathway are negative regulators for each other. Finally, the antitumor activity of POS was confirmed in GBM xenograft models in vivo. Consistent with the in vitro conclusions, POS upregulated the expression of LC3 and decreased the expression of CD133, survivin and ß-catenin, as shown by the immunohistochemistry analysis. In summary, this work provides an experimental foundation for exploiting POS as a CSCs-targeting antitumor drug for GBM treatment. [ABSTRACT FROM AUTHOR]

Myeloid neoplasms arise from malignant primitive cells, which exhibit growth advantage within the bone marrow microenvironment (BMM). The interaction between these malignant cells and BMM cells is critical for the progression of these diseases. Extracellular vesicles (EVs) are lipid bound vesicles secreted into the extracellular space and involved in intercellular communication. Recent studies have described RNA and protein alterations in EVs isolated from myeloid neoplasm patients compared to healthy controls. The altered expression of various micro-RNAs is the best-described feature of EVs of these patients. Some of these micro-RNAs induce growth-related pathways such as AKT/mTOR and promote the acquisition of stem cell-like features by malignant cells. Another well-described characteristic of EVs in myeloid neoplasms is their ability to suppress healthy hematopoiesis either via direct effect on healthy CD34+ cells or via alteration of the differentiation of BMM cells. These results support a role of EVs in the pathogenesis of myeloid neoplasms. mainly through mediating the interaction between malignant and BMM cells, and warrant further study to better understand their biology. In this review, we describe the reported alterations of EV composition in myeloid neoplasms and the recent discoveries supporting their involvement in the development and progression of these diseases. [ABSTRACT FROM AUTHOR]

Caffeic acid (CA), ferulic acid (FA) and caffeic acid phenethyl ester (CAPE) have a broad anticancer effect on various cell lines. In this study, nine ferulic and caffeic acid-based 1,2,4 and 1,3,4 oxadiazole molecular hybrids were synthesized and their cytotoxic activity was evaluated mainly against Glioblastoma (GBM) cell lines. Compounds 1 and 5 exhibited the highest inhibitory activity against three different GBM cell lines (LN229, T98G, and U87), without toxicity to healthy human mesenchymal stem cells (hMSC). In addition, their cytotoxicity was also evaluated against three additional cancer cell lines and more inhibitory results were found than GBM cell lines. The IC50 values of compound 5 in U87, T98G, LN229, SKOV3, MCF7, and A549 cells were determined as 35.1, 34.4, 37.9, 14.2, 30.9, and 18.3 µM. In the light of biological activity studies, the developed compounds have a high potential to lead studies for the development of new drug candidates for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Even though various treatment methods are available for cancer, the death curve is not reducing. The diagnosis of cancer at the fourth stage and drug resistance are the leading reasons for treatment failure and lower survival rates. In this review article, we summarize the possible pitfalls during cancer treatment in general, which mainly include multidrug resistance, and propose a hypothesis for colorectal cancer specifically. We also evaluate multidrug resistance in cancer in general and colorectal cancer in particular and hypothesize a concept based on combination therapy with 5-fluorouracil, curcumin, and lipids for the possible management of colorectal cancer. In addition, a hypothetical approach, combining a synthetic agent and a natural chemotherapeutic agent, to treating colorectal cancer is also discussed. This hypothesis could improve the management of colorectal cancer. [ABSTRACT FROM AUTHOR]

PI3Kβ is required for invadopodia‐mediated matrix degradation by breast cancer cells. Invadopodia maturation requires GPCR activation of PI3Kβ and its coupling to SHIP2 to produce PI(3,4)P2. We now test whether selectivity for PI3Kβ is preserved under conditions of mutational increases in PI3K activity. In breast cancer cells where PI3Kβ is inhibited, short‐chain diC8‐PIP3 rescues gelatin degradation in a SHIP2‐dependent manner; rescue by diC8‐PI(3,4)P2 is SHIP2‐independent. Surprisingly, the expression of either activated PI3Kβ or PI3Kα mutants rescued the effects of PI3Kβ inhibition. In both cases, gelatin degradation was SHIP2‐dependent. These data confirm the requirement for PIP3 conversion to PI(3,4)P2 for invadopodia function and suggest that selectivity for distinct PI3K isotypes may be obviated by mutational activation of the PI3K pathway. [ABSTRACT FROM AUTHOR]

Cellular senescence is traditionally considered as stable cell cycle arrest state with other phenotypic alterations including the production of an array of cytokines and growth factors. Cancer cells undergo senescence in response to chemotherapeutic agents, radiotherapy and molecular targeted therapy. This form of senescence is termed therapy-induced senescence (TIS) and represents a desirable target in cancer therapy. Recent studies have shown that cellular senescence is a highly heterogeneous and dynamic process. Apart from being cleared by the immune system, the senescent cancer cells may survive for a long time and escape from senescence state. Notably, these cells even have the potential to regain stem-like state with high aggressiveness that eventually facilitates cancer recurrence. Furthermore, the senescence-associated secretory phenotype (SASP) of senescent cells is not always the same, and could establish immunosuppression and a protumor microenvironment. Given these detrimental effects, senescence-inducing chemotherapy followed by senotherapy (the "one–two punch" approach), has emerged. This combined therapy could mitigate unnecessary side effects of the persistent senescent cells, reduce the toxicity of pro-senescence therapy and prolong the survival of cancer patients, and it has a potential future in the precise treatment of cancer. Herein, we review the complex effects of therapy-induced senescence in cancer and highlight the great promise of two-step strategies in anticancer therapies. [ABSTRACT FROM AUTHOR]

Background: Telomerase reverse transcriptase (TERT) promoter mutations play a role in carcinogenesis and are found in both tumors and cancer cell lines. TERT promoter methylation, transcription factor binding, chromatin remodeling, and alternative splicing are also known to play an integral role in TERT regulation. Methods: Using nanopore Cas9 targeted sequencing, we characterized allele-specific methylation in thyroid cancer cell lines heterozygous for the TERT promoter mutation. Furthermore, using chromatin immunoprecipitation followed by Sanger sequencing, we probed allele-specific binding of the transcription factors GABPA (GA binding protein transcription factor subunit alpha) and MYC, as well as the chromatin marks H3K4me3 and H3K27me3. Finally, using coding single nucleotide polymorphisms and the long-read sequencing, we examined complementary DNA for monoallelic expression (MAE). Results: We found the mutant TERT promoter allele to be significantly less methylated than wild type, while more methylated in the gene body in heterozygous TERT mutant cell lines. We demonstrated that the transcriptional activators GABPA and MYC bind only to the mutant TERT allele. In addition, the activating and repressive chromatin marks H3K4me3 and H3K27me3, respectively, bind mutant and wild-type alleles exclusively. Finally, in heterozygous mutant cell lines, TERT exhibits MAE from the mutant allele only. Conclusions: In summary, by employing new long-read sequencing methods, we were able to definitively demonstrate allele-specific DNA methylation, histone modifications, transcription factor binding, and the resulting monoallelic transcription in cell lines with heterozygous TERT mutations. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is closely related to metabolic syndrome. We investigated the effect of a Psoralea corylifolia L. (PC) seeds extract (PCE) on NAFLD. PC seeds were extracted using different ethanol concentrations to produce five extracts, and the 70% ethanol PCE, which had the highest phenolic content, was used in subsequent in vitro and in vivo experiments. The inhibitory effect of PCE on hepatic steatosis was estimated using HepG2 cells treated with oleic acid (OA). In addition, an in vivo NAFLD model was established using high‐fat diet (HFD)‐induced obese C57BL/6 mice. Obesity was induced in mice over 14 weeks. PCE (100 or 200 mg/kg/day) was administered orally to mice after 8 weeks of the 14‐week treatment period for 6 weeks. PCE suppressed lipid accumulation in OA‐treated HepG2 cells. PCE ameliorated the antioxidant activity suppressions induced by the HFD. In addition, both PCE100 and PCE200 groups reduced lipid accumulation and the expression levels of inflammatory proteins as compared with HFD group. PCE administration significantly attenuated hepatic steatosis in liver tissues by decreasing the expression of lipogenic protein sterol regulatory element binding protein 1‐c (SREBP‐1c) and its downstream protein fatty acid synthase (FAS) in HFD‐fed mice and in OA‐treated HepG2 cells. Furthermore, PCE administration increased the phosphorylation of AMP‐activated protein kinase (AMPK) and acetyl‐CoA carboxylase. These results suggest that PCE could be used as a functional material to prevent or ameliorate NAFLD by inhibiting lipid accumulation in liver. Practical Application: Psoralea corylifolia L. is rich in polyphenol and other phytochemicals. In this study, we identified the beneficial effects of Psoralea corylifolia L. extract on hepatic steatosis in oleic‐acid‐induced HepG2 cells and high‐fat diet‐fed mice. The result of this study will provide the evidence that a Psoralea corylifolia L. extract has potential use as a functional material for the prevention and amelioration of nonalcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

Cross-talk between tumor cells and mechanical stress in the tumor microenvironment has been shown to be involved in carcinogenesis. High mechanical stress in tumors can alter the metabolism and behaviors of cancer cells and cause cancer cells to attain cancer stem-like cell properties, thus driving tumor progression and promoting metastasis. The mechanical signal is converted into a biochemical signal that activates tumorigenic signaling pathways through mechanotransduction. Herein, we describe the physical changes occurring during reprogramming of cancer cell metabolism, which regulate cancer stem cell functions and promote tumor progression and aggression. Furthermore, we highlight emerging therapeutic strategies targeting mechanotransduction signaling pathways. [ABSTRACT FROM AUTHOR]

Breast cancer is a heterogeneous disease, with a morbidity rate of 27.8% and a mortality rate of 15% among women population worldwide. Understanding how this cancer develops and the mechanisms behind tumor progression and chemoresistance is of utmost importance. Exosomes mediate communication in a population of heterogeneous tumoral cells. They have a cargo composed of oncogenes and oncomiRs which change the transcriptomic scenario of their targeted cells and activate numerous tumor‐promoting signaling pathways. Exosomes secreted by breast cancer cells lead to enhanced cell proliferation, replicative immortality, angiogenesis, invasion, migration, and chemoresistance. Studying exosomes from this perspective offers more in depth understanding of breast malignancy and may aid in the future development of early diagnostic, prognostic and therapeutic options. We present the latest findings in this area and offer practical solutions which may further stimulate the much‐needed research of exosome in breast cancer. [ABSTRACT FROM AUTHOR]

Biosynthesis of silver nanoparticles (AgNPs) from the medicinal plants has been considered as a remarkable approach of several therapeutic innovations and successful drug delivery. Silver nanoparticles were biosynthesized with Salvia miltiorrhiza, Chinese medicinal herb and assessed for its anticarcinogenic property. Synthesis of AgNPs was characterized by several studies such as UV-absorbance and it shows peak values in the range of 425–445 nm. The sizes of the nanoparticles are confirmed by dynamic light scattering analysis and it shows 100 nm. Furthermore, transmission electron microscopy (TEM) and energy dispersive X-ray analysis (EDX) was to confirm the shape and Ag particles are present in the synthesized materials. FTIR analysis to find out the active biomolecules located in the surface of the synthesized particles. This AgNPs from S. miltiorrhiza inhibits the growth of Bacillus subtillis, Staphylococcus aureus, Escherichia coli, and Klebsiella pneumonia. Furthermore, the anticancer potential of AgNPs is examined in prostate adenocarcinoma (LNCaP) cell lines. In this study, we found the AgNPs effectively induces cytotoxicity, ROS and apoptosis by modulation of intrinsic apoptoic Bcl2, Bclxl, Bax and Caspase 3 protein expressions in LNCap cell lines. Based on the study, synthesis of AgNPs from S. miltiorrhiza shows eco-friendly and it exhibits antimicrobial and anticarcinogenic effects. [ABSTRACT FROM AUTHOR]

Cervical cancer is the third most common highest mortality in women worldwide. The use of standard chemotherapeutic drugs against cervical cancer patients received several side effects. Therefore, we focused phytoconsituents-mediated synthesis of gold nanoparticles (AuNPs) considered as greatest attention in the treatment of cervical cancer. In this present study, we reported that green synthesis of AuNPs by using with Alternanthera Sessilis aqueous extract. Synthesis of AuNPs were characterized by UV visible spectroscopy, energy dispersive X-ray (EDX), selected area diffraction pattern (SAED), Fourier transform infrared spectroscopy (FTIR), high-resolution transmission electron microscopy (HR-TEM) and atomic force microscope. Synthesized AuNPs confirmed by the UV absorption maximum at 535 and crystal structure of gold AuNPs was further confirmed by EDX and SAED. TEM and atomic force microscopy images show the size and morphological distribution of nanoparticles. FTIR analysis was confirmed the hydroxyl groups, amine and alkaline groups of biomolecules are present in the AuNPs. Moreover, AuNPs induce cytotoxicity in cervical cancer cells and also induce apoptosis through modulating intrinsic apoptotic mechanisms in cervical cancer cells. This green synthesis of AuNPs from Alternanthera sessilis approach was easy, large scaled up and eco-friendly. [ABSTRACT FROM AUTHOR]

Silibinin, a polyphenolic flavonolignan, is well‐known as a safe therapeutic drug without any side effects in the treatment of many malignancies especially cancerous cells. In this study, to overcome problems such as low solubility of silibinin and to enhance its delivery to cancerous cells, we encapsulated silibinin in polymersome nanoparticles. Physicochemical measurements such as dynamic light scattering, transmission electron microscopy, scanning electron microscopy, and atomic force microscopy confirmed the proper encapsulation of silibinin in nanoparticles. Furthermore, antiproliferative and apoptotic activities of silibinin encapsulated in polymersome nanoparticles (SPNs) on MDA‐MB‐231 breast cancer cell line were validated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, Annexin V/Propidium Iodide measurement, and cell cycle analysis. In addition, quantitative reverse transcription polymerase chain reaction analysis confirmed that SPNs can repress oncogenic microRNAs (miRNAs) such as miR‐125b and miR‐182, as well as antiapoptotic genes such as Bcl2. SPNs can also induce overexpression of proapoptotic target genes such as P53, CASP9, and BAX directly and/or indirectly (through regulation of miRNAs). Our results suggested that polymersomes can be used as stable carriers in nano‐dimensions and SPNs can be considered as a promising pharmacological agent for cancer therapy. [ABSTRACT FROM AUTHOR]

This research aimed to evaluate the effects of silymarin (SM)-loaded polymeric micelles (PMs) on the renal toxicity and anticancer activity of cisplatin. Amphiphilic chitosan derivatives were employed to develop SM-loaded PMs. The permeation across an intestinal membrane, cytotoxicity, and renal toxicity of cisplatin during the treatment were evaluated. The SM-loaded PMs had small particle sizes (326–336 nm), negative surface charge, high entrapment efficiency (47–70%), and demonstrated pH-sensitive release. Rapid drug release was obtained at pH 7.4 (81–87% in 4 h). The SM-loaded PMs exhibited higher flux than free SM. Moreover, the pretreatment of SM (50–100 μg/mL)-loaded PMs increased the killing efficacy of cisplatin on the cancer cells. The renoprotective effect was witnessed (p < 0.05) on the cells pretreated with SM-loaded benzyl-functionalized succinyl chitosan (BSC) PMs compared with those treated with only cisplatin, which the % cell viability increased from 29% to 82% and 96% for the PMs with SM concentration of 50 and 100 μg/mL, respectively. Moreover, the reduction in cell apoptosis and necrosis induced by cisplatin has been observed. In conclusion, SM-loaded BSC PMs could improve the bioavailability of SM, enhance the therapeutic effect, and protect renal damage during the treatment with cisplatin. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PaC) is characterized by a highly inflammatory tumor microenvironment, and inflammatory mediators are implicated in the progression of this cancer. Regenerating gene protein (Reg) 3A is significantly upregulated during pancreatic inflammation, and has been demonstrated to serve an important role during PaC progression, based on its increased expression levels in PaC and potent cell proliferation-promoting activity. The aim of the present study was to investigate the effect of eckol, a phlorotannin compound with a variety of biological activities including anti-inflammatory, anti-tumor and cytoprotective effects, on Reg3A-induced proliferation of human SW1990 PaC cells. SW1990 cells were pre-treated with eckol for 48 h at concentrations of 5, 10 and 20 µg/ml. Subsequently, Reg3A protein was added to the culture media at a final concentration of 50 ng/ml in the presence or absence of eckol for 24 h. The cytotoxicity and proliferative capacity of the SW1990 cells was determined using an MTT and flow cytometry analysis. Cell colony formation was also used to determine the effect of eckol on the anchorage-independent growth and colony-forming capacity of Reg3A-treated PaC cells. The expression levels of cyclin D1, STAT3, JAK2, and NF-κB p65 were measured with reverse transcription-quantitative PCR and western blotting. Eckol reduced Reg3A-promoted cell survival, inhibited Reg3A-induced cell cycle progression and inhibited colony growth of SW1990 cells in soft agar in a concentration-dependent manner. Additionally, the Reg3A-mediated upregulation of expression of JAK2, STAT3, NF-κBp65 and cyclin D1 was reduced when treated with eckol. Reg3A is upregulated during pancreatic inflammation and exhibits a pro-growth function and may thus serve a critical role during inflammation-driven PaC malignancies. Eckol may be a potential protective agent against progression of PaC accompanied by pancreatic inflammation. [ABSTRACT FROM AUTHOR]

Grape pomace is the source of bioactive compounds (anthocyanins, flavonols, flavan‐3‐ols, and stilbenes) which exhibit antiproliferative actions on cell cultures. We have investigated the antitumoral effects of grape pomace and grape seed extracts on colon cancer cells (Caco‐2, HT‐29) and fibroblasts. Crude extracts prepared from white and red pomace, and grape seeds, reduced the viability and proliferation of Caco‐2. HT‐29 cells were resistant to these actions. Purified extracts were then prepared from the same sources and compared with the LDH test; again, all three extracts were active and purified extract from grape seed was the most potent and specific on Caco‐2 cells. HT‐29 cells were more sensitive to these purified extracts. The biological activity resided almost exclusively in the flavonol and flavan‐3‐ols subfractions, rather than the anthocyanin subfraction. Preliminary results on the mechanisms involved in these effects revealed downregulation of Myc gene expression in HT‐29 and upregulation of Ptg2 in Caco‐2 cells. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are innately immune to the body's immune system and can actively recognize and kill cancer cells. This study explores the potential for enhancing the killing ability of NK cells by co-culturing the NK cells with the target cells under a static magnetic field (SMF). In this study, NK92-MI cell lines were cultured in the presence of a 0.4-T SMF. The effect of the SMF on NK cell viability was evaluated by means of an MTT assay. Culturing tests were performed with inhibitors of the DAG/IP3, STAT3, ERK, JNK and p38 pathways in order to examine the possible signaling cascade responsible for the SMF effect on the NK92-MI cell viability. Finally, the effect of the SMF on the cytotoxicity of the NK92-MI cells was evaluated by co-culturing the NK cells with K562 leukemia cell lines. The results showed that the application of a 0.4-T SMF significantly increased (p < 0.05) the viability of the NK92-MI cells. Furthermore, the inhibitor tests indicated that the SMF affected cell viability by activating multiple MAPK signaling pathways (ERKs, JNKs, and p38-MAPK). Finally, SMF pre-exposure for 48 hr significantly improved the killing activity of the NK92-MI cells (p < 0.05). That is, pre-exposure to SMF increased the viability of the NK92-MI cells and improved their killing ability against K562 tumor cells. In general, the present results suggest that NK cells pre-exposed to 0.4-T SMF show potential as a tool for immune-therapy treatment of cancer. [ABSTRACT FROM AUTHOR]

In this study, an efficient method to enhance phenolic compound production in the in vitro cultured shoots of Polyscias filicifolia was developed. The phenolic compound content in P. filicifolia has not yet been reported. Shoots were treated with methyl jasmonate (JM) or salicylic acid (SA) at doses of 50, 100, or 200 μM. HPLC-UV-VIS and LC-MS techniques were used for the determination of chlorogenic, caffeic, and ferulic acids. The total phenolics and flavonoids were quantified, and the antioxidant capacity of plant extracts was determined using DPPH and ABTS methods. Finally, the cytotoxic activity of P. filicifolia extracts in normal (HaCaT) and cancer (A549) cells was investigated. Further, the effect of the extracts on cisplatin cytotoxicity was assessed. The elicitors significantly enhanced phenolic production compared to that in untreated shoots and leaves of intact plants. Chlorogenic acid was the most abundant compound with the highest yield of 5.03 ±0.25 mg/g DW after treatment with 50 μM SA. The total flavonoid and phenolic content was significantly and dose-dependently influenced by JM. The highest antioxidant capacity was noted in extracts derived from shoots grown on media supplemented with 50 μM SA and 200 μM JM; these doses were used for further cytotoxic activity investigations. The extracts from JM or SA treatments reduced cancer cell viability and increased their mortality, whereas the extract from JM treatment exhibited protective effect on normal cells. Moreover, the comparison of cytotoxic properties of plant extracts and cisplatin indicated that plant phenolic compounds in combination with anticancer drugs could reduce the detrimental effect of the latter on human cells. [ABSTRACT FROM AUTHOR]

There are growing interests in the health benefits associated with consumption of fruits and vegetables, especially for the prevention of cancer, cardiovascular, or other chronic diseases. Epidemiological studies and clinical trials suggest that these health benefits are strongly associated with phytochemicals found in fruits and vegetables. Ursolic acid is a naturally synthesized pentacyclic triterpenoid, widely distributed in different fruits and vegetables. Current research suggested that ursolic acid and its derivatives exhibited anticancer activity, anti-inflammatory effects, and induction of apoptosis in several human cancer cells. In particular, ursolic acid inhibited breast cancer proliferation by inducing cell G1/G2 arrest and regulating the expression of key proteins in signal transduction pathways. In addition, ursolic acid induced apoptosis in human breast cancer cells through intrinsic and extrinsic apoptotic pathways. Ursolic acid was also determined to scavenge free radicals and have potent anti-inflammation activity. The purpose of this paper is to review recent literature on anticancer activity of ursolic acid and focus on its mechanisms of action. [ABSTRACT FROM AUTHOR]

The intestine is maintained by stem cells located at the base of crypts and distinguished by the expression of LGR5. Genetically engineered mouse models have provided a wealth of information about intestinal stem cells, whereas less is known about human intestinal stem cells owing to difficulty detecting and isolating these cells. We established an organoid repository from patient-derived adenomas, adenocarcinomas and normal colon, which we analyzed for variants in 71 colorectal cancer (CRC)-associated genes. Normal and neoplastic colon tissue organoids were analyzed by immunohistochemistry and fluorescentactivated cell sorting for LGR5. LGR5-positive cells were isolated from four adenoma organoid lines and were subjected to RNA sequencing. We found that LGR5 expression in the epithelium and stroma was associated with tumor stage, and by integrating functional experiments with LGR5-sorted cell RNA sequencing data fromadenoma and normal organoids, we found correlations between LGR5 and CRC-specific genes, including dickkopf WNT signaling pathway inhibitor 4 (DKK4) and SPARC-related modular calcium binding 2 (SMOC2). Collectively, this work provides resources, methods and new markers to isolate and study stem cells in human tissue homeostasis and carcinogenesis. [ABSTRACT FROM AUTHOR]

Chrysin, as a flavone, is a promising drug candidate because of its multifaceted properties, such as anti-inflammatory, antioxidant and anticancer. However, its poor bioavailability is a bottleneck for pharmaceutical applications. To enhance the bioactive effects, chrysin-loaded poly (D,L-lactic-co-glycolic acid) and polyvinyl alcohol were successfully prepared to overcome problems associated with chrysin. The properties of modified nanochrysin were analysed by in vitro dissolution study, XRD, FTIR and SEM. Free radical scavenging potentials of the modified nanochrysin against DPPH were confirmed based on its stable antioxidant effects. A DNA instability enhancement was observed after H2O2 exposure, whereas chrysin decreased the H2O2 activity, and modified nanochrysin was more potent in this regard. Blood compatibility on red blood cells was confirmed by haemolytic and in vitro cytotoxicity assays. The in vitro anticancer activity of the modified nanochrysin towards MCF-7 and SKOV-3 cell lines using various parameters was investigated. The nanochrysin was found to exert cell growth arrest against both cancer cells in a dose-dependent manner. IC50 value was significantly decreased in nanochrysin in comparison with pure chrysin and induced apoptotic cell death pathway. The results of this study suggest that the nanochrysin might be used for medical applications and offer a beneficial formulation for chemotherapy. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (AgNPs) have been undeniable for its antimicrobial activity while its antitumour potential is still limited. Therefore, the present study focused on determining cytotoxic effects of AgNPs on Michigan cancer foundation-7 (MCF-7) breast cancer cells and its corresponding mechanism of cell death. Herein, the authors developed a bio-reduction method for AgNPs synthesis using actinomycetes isolated from marine soil sample. The isolated strain was identified by 16s ribotyping method and it was found to be Streptomyces atrovirens. Furthermore, the synthesised AgNPs were characterised by various bio-analytical techniques such as ultraviolet-visible spectrophotometer, atomic force microscopy, transmission electron microscopy, Fourier transform infra-red spectroscopy, and X-ray diffraction. Moreover, the results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay reveals 44.51 μg of AgNPs to have profound inhibition of cancer cell growth; furthermore, the inhibition of MCF-7 breast cancer cell line was found to be dose dependent on treatment with AgNPs. Acridine orange and ethidium bromide double staining methods were performed for cell morphological analysis. The present results showed that biosynthesised AgNPs might be emerging alternative biomaterials for human breast cancer therapy. [ABSTRACT FROM AUTHOR]

In this research, we synthesized a novel caffeic acid-functionalized iron oxide nanoparticles (CFA-functionalized SPION) L929 (mouse fibroblast cell), U87 (glioblastoma brain cancer cell), MCF-7 (breast cancer cell), HeLa (cervix cancer cell), and A549 (human lung cancer cell) cell lines. Thermal decomposition and Stöber methods were used to prepare APTES-capped SPION, respectively. The carboxylated polyethylene glycol (PEG-COOH), folic acid (FA), and caffeic acid (CFA) were attached to the surface of SPION via carboxylic/amine groups. Structural analysis (Rietveld analysis) confirmed the phase purity of the product. The conjugation of organics to the surface of SPION was followed with FT-IR spectroscopy and thermal gravimetric analysis (TGA). SEM analysis presented the spherical morphology of product with 13 ± 3 nm particle size. And also, superparamagnetic property of product was deduced from VSM analysis. Uptake of CFA-functionalized SPION from the cell and release of CFA from CFA-functionalized SPION has been studied by using Prussian blue staining and spectrophotometer, respectively. Also, cell viability and cytotoxicity was tested by MTT and LDH assays. The uptake of CFA-functionalized SPION by HeLa, MCF-7, and U87 was higher than A549 and L929 cells. Also, caffeic acid release from CFA-functionalized SPION increased at an acidic environment (pH 4.4). A newly synthesized CFA-functionalized SPION in all used concentrations decreased cell viability and increased cytotoxicity at 24th and 48th hours. The results showed that the CFA-functionalized SPION is a potential anticancer agent for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Nutrient deprivation, hypoxia, radiotherapy and chemotherapy induce endoplasmic reticulum (ER) stress, which activates the so-called unfolded protein response (UPR). Extensive and acute ER stress directs the UPR towards activation of death-triggering pathways. Cancer cells are selected to resist mild and prolonged ER stress by activating pro-survival UPR. We recently found that drug-resistant tumor cells are simultaneously resistant to ER stress-triggered cell death. It is not known if cancer cells adapted to ER stressing conditions acquire a chemoresistant phenotype. Methods: To investigate this issue, we generated human cancer cells clones with acquired resistance to ER stress from ER stress-sensitive and chemosensitive cells. Results: ER stress-resistant cells were cross-resistant to multiple chemotherapeutic drugs: such multidrug resistance (MDR) was due to the overexpression of the plasma-membrane transporter MDR related protein 1 (MRP1). Gene profiling analysis unveiled that cells with acquired resistance to ER stress and chemotherapy share higher expression of the UPR sensor protein kinase RNA-like endoplasmic reticulum kinase (PERK), which mediated the erythroid-derived 2-like 2 (Nrf2)-driven transcription of MRP1. Disrupting PERK/Nrf2 axis reversed at the same time resistance to ER stress and chemotherapy. The inducible silencing of PERK reduced tumor growth and restored chemosensitivity in resistant tumor xenografts. Conclusions: Our work demonstrates for the first time that the adaptation to ER stress in cancer cells produces a MDR phenotype. The PERK/Nrf2/MRP1 axis is responsible for the resistance to ER stress and chemotherapy, and may represent a good therapeutic target in aggressive and resistant tumors. [ABSTRACT FROM AUTHOR]

Fine needle aspiration cytology (FNAC) represents the gold standard for determining the nature of thyroid nodules. It is a reliable method with good sensitivity and specificity. However, indeterminate lesions remain a diagnostic challenge and researchers have contributed molecular markers to search for in cytological material to refine FNAC diagnosis and avoid unnecessary surgeries. Nowadays, several “home-made” methods as well as commercial tests are available to investigate the molecular signature of an aspirate. Moreover, other markers (i.e., microRNA, and circulating tumor cells) have been proposed to discriminate benign from malignant thyroid lesions. Here, we review the literature and provide data from our laboratory on mutational analysis of FNAC material and circulating microRNA expression obtained in the last 6 years. [ABSTRACT FROM AUTHOR]

Past studies have shown that the Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) is commonly downregulated in gastric cancer, which contributes to elevated activation of PI3K/Akt signaling, proliferation and tumorigenesis of gastric cancer cells. However, the mechanisms underlying the reduced expression of SHIP2 in gastric cancer remain unclear. While gene copy number variation analysis and exon sequencing indicated the absence of genomic alterations of SHIP2, bisulfite genomic sequencing (BGS) showed promoter hypomethylation of SHIP2 in gastric cancer cells. Analysis of transcriptional activity of SHIP2 promoter revealed Specificity protein 1 (Sp1) was responsible for the regulation of SHIP2 expression in gastric cancer cells. Furthermore, Sp1 expression, but not Sp3, was frequently downregulated in gastric cancer compared with normal gastric mucosa, which was associated with a paralleled reduction in SHIP2 levels in gastric cancer. Moreover, overexpression of Sp1 inhibited cell proliferation, induced apoptosis, suppressed cell motility and invasion in gastric cancer cells in vitro, which was, at least in part, due to transcriptional activation of SHIP2 mediated by Sp1, thereby inactivating Akt. Collectively, these results indicate that decreased expression of transcription factor Sp1 contributes to suppression of SHIP2 in gastric cancer cells. [ABSTRACT FROM AUTHOR]

Oncolytic viruses (OVs) are capable of exerting anti-cancer effects by a variety of mechanisms, including immune-mediated tumor cell death, highlighting their potential use in immunotherapy. Several adaptation mechanisms such as autophagy contribute to OV-mediated anti-tumor properties. Autophagy regulates immunogenic signaling during cancer therapy which can be utilized to design therapeutic combinations using approaches that either induce or block autophagy to potentiate the therapeutic efficacy of OVs. In this article, we review the complicated interplay between autophagy, cancer, immunity, and OV, summarize recent progress in the contribution of OV-perturbed autophagy to oncolytic immunity, and discuss the challenges in targeting autophagy to enhance oncolytic immunotherapy. [ABSTRACT FROM AUTHOR]

Plant derived phenolic compounds have been shown to inhibit the initiation and progression of cancers by modulating genes regulating key processes such as: (a) oncogenic transformation of normal cells; (b) growth and development of tumors; and (c) angiogenesis and metastasis. Recent studies focusing on identifying the molecular basis of plant phenolics-induced cancer cell death have demonstrated down-regulation of: (a) oncogenic survival kinases such as PI3K and Akt; (b) cell proliferation regulators that include Erk1/2, D-type Cyclins, and Cyclin Dependent Kinases (CDKs); (c) transcription factors such as NF-kβ, NRF2 and STATs; (d) histone deacetylases HDAC1 and HDAC2; and (e) angiogenic factors VEGF, FGFR1 and MIC-1. Furthermore, while inhibiting oncogenic proteins, the phenolic compounds elevate the expression of tumor suppressor proteins p53, PTEN, p21, and p27. In addition, plant phenolic compounds and the herbal extracts rich in phenolic compounds modulate the levels of reactive oxygen species (ROS) in cells thereby regulate cell proliferation, survival and apoptosis. Furthermore, recent studies have demonstrated that phenolic compounds undergo transformation in gut microbiota thereby acquire additional properties that promote their biological activities. In vitro observations, preclinical and epidemiological studies have shown the involvement of plant phenolic acids in retarding the cancer growth. However, to date, there is no clinical trial as such testing the role of plant phenolic compounds for inhibiting tumor growth in humans. More over, several variations in response to phenolic acid rich diets-mediated treatment among individuals have also been reported, raising concerns about whether phenolic acids could be used for treating cancers. Therefore, we have made an attempt to (a) address the key structural features of phenolic acids required for exhibiting potent anti-cancer activity; (b) review the reported findings about the mechanisms of action of phenolic compounds and their transformation by gut microbiota; and (c) update the toxicological aspects and anti-tumor properties of phenolic compounds and extracts containing phenolic compounds in animals. [ABSTRACT FROM AUTHOR]

Invadopodia and podosomes, collectively referred to as invadosomes, are F-actin-rich basal protrusions of cells that provide sites of attachment to and degradation of the extracellular matrix. Invadosomes promote the invasion of cells, ranging from metastatic cancer cells to immune cells, into tissue. Here, we show that neuronal growth cones form protrusions that share molecular, structural and functional characteristics of invadosomes. Growth cones from all neuron types and species examined, including a variety of human neurons, form invadosomes both in vitro and in vivo. Growth cone invadosomes contain dynamic F-actin and several actin regulatory proteins, as well as Tks5 and matrix metalloproteinases, which locally degrade the matrix. When viewed using three-dimensional superresolution microscopy, F-actin foci often extended together with microtubules within orthogonal protrusions emanating fromthe growth cone central domain. Finally, inhibiting the function of Tks5 both reduced matrix degradation in vitro and disrupted motoneuron axons from exiting the spinal cord and extending into the periphery. Taken together, our results suggest that growth cones use invadosomes to target protease activity during axon guidance through tissues. [ABSTRACT FROM AUTHOR]

A hallmark of cancer is resistance to apoptosis, with both the loss of proapoptotic signals and the gain of anti-apoptotic mechanisms contributing to tumorigenesis. As inducing apoptosis in malignant cells is one of the most challenging tasks regarding cancer, researchers increasingly focus on natural products to regulate apoptotic signaling pathways. Curcumin, a polyphenolic derivative of turmeric, is a natural compound derived from Curcuma longa, has attracted great interest in the research of cancer during the last half century. Extensive studies revealed that curcumin has chemopreventive properties, which are mainly due to its ability to arrest cell cycle and to induce apoptosis in cancer cells either alone or in combination with chemotherapeutic agents or radiation. The underlying action mechanisms of curcumin are diverse and has not been elucidated so far. By regulating multiple important cellular signalling pathways including NF-κB, TRAIL, PI3 K/Akt, JAK/STAT, Notch-1, JNK, etc., curcumin are known to activate cell death signals and induce apoptosis in pre-cancerous or cancer cells without affecting normal cells, thereby inhibiting tumor progression. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy. This article reviews the main effects of curcumin on the different apoptotic signaling pathways involved in curcumin induced apoptosis in cancer cells via cellular transduction pathways and provides an in depth assessment of its pharmacological activity in the management of tumor progression. [ABSTRACT FROM AUTHOR]

Curcumin, a phytochemical derived from the rhizome of Curcuma longa, is a very potent inducer of cancer cell death. It is believed that cancer cells are more sensitive to curcumin treatment than normal cells. Curcumin has been shown to act as a prooxidant and induce DNA lesions in normal cells. We were interested in whether curcumin induces DNA damage and the DNA damage response (DDR) signalling pathway leading to apoptosis in normal resting human T cells. To this end, we analysed DNA damage after curcumin treatment of resting human T cells (CD3+) and of proliferating leukaemic Jurkat cells by the fluorimetric detection of alkaline DNA unwinding (FADU) assay and immunocytochemical detection of γ-H2AX foci. We showed that curcumin-treated Jurkat cells and resting T cells showed neither DNA lesions nor did they activate key proteins in the DDR signalling pathway, such as phospho-ATM and phospho-p53. However, both types of cell were equally sensitive to curcumin-induced apoptosis and displayed activation of caspase-8 but not of DNA damage-dependent caspase-2. Altogether, our results revealed that curcumin can induce apoptosis of normal resting human T cells that is not connected with DNA damage. [ABSTRACT FROM PUBLISHER]

Aim: To determine the radiosensitizing effect of sesamol in cervical carcinoma cell line (HeLa) in vitro. Materials and Methods: Sesamol-pretreated (10 µg/ml) HeLa cells were exposed to 4 Gy γ-radiation and the cellular changes were estimated by lipid peroxidation, changes in the enzymatic and non-enzymatic antioxidant status, oxidative DNA damage, % of growth inhibition, and morphological changes in the irradiated and/or sesamol-treated HeLa cells. Results: Sesamol treatment prior to irradiation significantly increased the levels of thiobarbituric acid reactive substances, (TBARS), lipid hydroperoxides (LPH), and conjugated dienes (CD) in HeLa cells. On the other hand, sesamol treatment before irradiation significantly decreased the levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities (GPx). Further, we observed increased % tail DNA, tail length, and tail moment in sesamol plus γ-irradiated cells when compared to irradiation alone. The % of cell death was also increased in sesamol plus γ-irradiated cells, particularly at 48 h incubation. Conclusion: Sesamol pretreatment prior to irradiation enhances the radiation effects in HeLa cell line. This study supports the use of dietary phytochemicals such as sesamol in practical radiotherapy. [ABSTRACT FROM AUTHOR]