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Morphological changes of MCF 7 cells viewed under light microscope after exposure to: (A) Untreated, (B) 8.2 μM of BHMC for 48 h. Fluorescent microscopy of acridine orange and propidium iodide dual staining of human breast cancer cells lines (MCF-7) (C) untreated and (D) 8.2 μM of BHMC for 48 h. Note: Figures shown were representative of one of at least three independent replicates with similar parameter (magnification 100×).
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![Figure 5. Chemical structure of BHMC [8].](publication/349655790/figure/fig5/AS:995854332751874@1614441583245/Chemical-structure-of-BHMC-8_Q320.jpg)
(2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) is a synthetic curcumin analogue, which has been reported to possess anti-tumor, anti-metastatic, and anti-invasion properties on estrogen receptor (ER) negative breast cancer cells in vitro and in vivo. However, the cytotoxic effects of BHMC on ER positive breast cancer cells we...
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... morphological changes of untreated MCF-7 cells and MCF-7 cells treated with 8.2 μM of BHMC for 48 h are illustrated in Figure 1. With the 48 h of treatment, light microscopic observation ( Figure 1B) revealed that BHMC reduced the MCF-7 cells number and severely distorted the MCF-7 cells shape. ...
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... morphological changes of untreated MCF-7 cells and MCF-7 cells treated with 8.2 μM of BHMC for 48 h are illustrated in Figure 1. With the 48 h of treatment, light microscopic observation ( Figure 1B) revealed that BHMC reduced the MCF-7 cells number and severely distorted the MCF-7 cells shape. The treated MCF-7 cells underwent cell shrinkage and detachment. ...
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... treated MCF-7 cells underwent cell shrinkage and detachment. Meanwhile, the untreated MCF-7 cells ( Figure 1A) displayed normal and polygonal cells shape evidenced by the clear and distinctive cell membrane boundary. Fluorescent microscopic examination was performed on MCF-7 cells stained with acridine orange and propidium iodide to assess the presence of apoptosis in both untreated and BHMC-treated MCF-7 cells. ...
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... microscopic examination was performed on MCF-7 cells stained with acridine orange and propidium iodide to assess the presence of apoptosis in both untreated and BHMC-treated MCF-7 cells. As shown in Figure 1C, untreated MCF-7 cells were viable and emitted green fluorescence light with clear, intact, and rounded shapes. In contrast, treated MCF-7 cells ( Figure 1D) presented the morphological characteristics of apoptotic cells, which were evidenced by the presence of cells shrinkage and membrane blebbing as well as necrotic or late apoptotic morphological features, which emitted red fluorescence light. ...
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... shown in Figure 1C, untreated MCF-7 cells were viable and emitted green fluorescence light with clear, intact, and rounded shapes. In contrast, treated MCF-7 cells ( Figure 1D) presented the morphological characteristics of apoptotic cells, which were evidenced by the presence of cells shrinkage and membrane blebbing as well as necrotic or late apoptotic morphological features, which emitted red fluorescence light. ...
Citations
... The ability of BHMC to induce apoptosis was also reported in the MCF-7 cells with similar morphological characteristics. BHMC treatment caused decrease in the number of MCF-7 cells and resulted in severe deformation, including cell shrinkage and detachment, as well as progression to necrotic or late apoptosis stage (40). This was further confirmed by Syed Alwi et al. (5) in the morphological examination without any staining on HepG2 cells treated with BHMC that showed more apoptotic signs compared to HepG2 cells treated with curcumin. ...
Introduction: Natural bioactive substances have become increasingly noticeable for their capability to eliminate and counteract cancer throughout time. Curcumin, a bioactive compound derived from the rhizomes of turmeric, is well known for its therapeutic effect in inducing anti-inflammatory, anti-migration, and anti-proliferation activities. However, curcumin encounters several limitations that prevent it from reaching its maximum capabilities. One of the curcuminoid analogues, 2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone (BHMC), was synthesized by removing the unstable β-diketone moiety and changing into double bonds while retaining the hydroxyl group to improve the curcumin's bioavailability. It is aims to investigate the cytotoxicity of BHMC especially on the proliferation and migration effects towards human liver cancer, HepG2 cells. Methods: MTT assay was performed to determine the cytotoxicity of BHMC and curcumin on HepG2 and Hs27 cells. Next, Hoechst 33342 and Propidium Iodide staining were executed to observe the morphological changes on HepG2 cells treated with BHMC and curcumin. Further analysis on the migration rate of HepG2 cells upon treatment with BHMC and curcumin was measured using scratch assay. Results: At lower concentration, BHMC demonstrated approximately 3-7 times higher toxicity effect towards HepG2 cells compared to curcumin. BHMC also specifically targets HepG2 cells with a selectivity index of up to 6 units which clearly demonstrate its cytotoxic selectivity towards Hs27 cells. Further examination reveals that BHMC induces cytotoxicity via late-stage apoptosis. BHMC also enhanced the inhibition of the migration effects by 4.2, 7.2, and 7.6% throughout incubation period compared to the untreated and curcumin. Conclusion: Despite the pronounced toxicity of BHMC on HepG2 cells, BHMC was demonstrated more selective cytotoxic on Hs27.
... Nana Li et al. compared the efficiency effects of CUR-MSN-HA and CUR-MSN-PEI-FA in MDA-MB-231 and MCF-7 cell lines, consequently proving that CUR-MSN-polyethyleneimine (PEI)-FA is more effective at inducing the G2/M phase cell-cycle arrest [45]. The CUR analogue (2E,6E)-2,6-bis-(4hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) was shown to promote G2/M cell-cycle arrest and apoptosis in MCF-7 cells [46]. CUR increased apoptosis in blocked MDA-MB-231 cells at the G2 phase and inhibited the growth of TNBC by silencing EZH2 and restoring DLC1 expression [47]. ...
Breast cancer (BC) has become the fifth most prevalent cause of cancer-related morbidity, attracting significant attention from researchers due to its heightened malignancy and drug resistance. Conventional chemotherapy approaches have proven inadequate in addressing all BC subtypes, highlighting the urgent need for novel therapeutic approaches or drugs. Curcumin (CUR), a phytochemical derived from Curcuma longa (turmeric), has shown substantial potential in inhibiting BC cell migration, metastasis, and proliferation. However, the use of CUR in this context comes with challenges due to its dynamic and easily degradable nature, poor aqueous solubility, low bioavailability, rapid metabolism, and swift systemic elimination, collectively limiting its clinical applications. As such, we provide an overview of the properties, synthesis, and characterization of the hybridization of CUR and its analogue with chemo-drug building blocks. We reviewed research from the last five years on CUR’s biogenesis with respect to the regulation of BC, revealing that CUR participates in arresting BC cells in the cell cycle and significantly induces apoptosis in BC cells. Information on the chemotherapeutic and antitumor mechanisms of CUR in BC, including regulation of the cell cycle, increased cell apoptosis, and inhibition of multidrug resistance (MDR), was compiled. Additionally, we provide an overview of CUR loaded into nanomaterials that are cotreated with other chemotherapeutic drugs, such as paclitaxel, thymoquinone, and tamoxifen. In this review, we discuss different types of nanoparticles that can be used for CUR delivery, such as polymeric nanoparticles, carbon nanotubes, and liposomes. By comparing the size, entrapment efficiency, drug-loading capacity, release time, biocompatibility, pharmaceutical scale, and reproducibility of various nanomaterials, we aimed to determine which formulations are better suited for loading CUR or its analogue. Ultimately, this review is expected to offer inspiring ideas, promising strategies, and potential pathways for developing advanced anti-BC strategy nanosystems in clinical practice.
... Their findings suggested that introducing fluorine atom substitutions into SERDs enhanced overall therapeutic effectiveness, making them superior clinical candidates for orally treating ER-positive breast cancer. As for the top feature for ERβ, Pubchem777 ( Fig. 5D and Table 7), which relates to 4-methylcyclohexanol, when oxidized to cyclohexanone and its derivatives, serves as a valuable scaffold in the development of anticancer agents 67 Such compounds have the potential to act as potent inhibitors of tamoxifen-resistant MCF-7 cancer cells 68,69 . Consequently, the presence of these top features for ERα and ERβ inhibitors underscores the capability of our StackER model to discern the features of significant importance in the field of medicinal chemistry. ...
The role of estrogen receptors (ERs) in breast cancer is of great importance in both clinical practice and scientific exploration. However, around 15–30% of those affected do not see benefits from the usual treatments owing to the innate resistance mechanisms, while 30–40% will gain resistance through treatments. In order to address this problem and facilitate community-wide efforts, machine learning (ML)-based approaches are considered one of the most cost-effective and large-scale identification methods. Herein, we propose a new SMILES-based stacked approach, termed StackER, for the accelerated and efficient identification of ERα and ERβ inhibitors. In StackER, we first established an up-to-date dataset consisting of 1,996 and 1,207 compounds for ERα and ERβ, respectively. Using the up-to-date dataset, StackER explored a wide range of different SMILES-based feature descriptors and ML algorithms in order to generate probabilistic features (PFs). Finally, the selected PFs derived from the two-step feature selection strategy were used for the development of an efficient stacked model. Both cross-validation and independent tests showed that StackER surpassed several conventional ML classifiers and the existing method in precisely predicting ERα and ERβ inhibitors. Remarkably, StackER achieved MCC values of 0.829–0.847 and 0.712–0.786 in terms of the cross-validation and independent tests, respectively, which were 5.92–8.29 and 1.59–3.45% higher than the existing method. In addition, StackER was applied to determine useful features for being ERα and ERβ inhibitors and identify FDA-approved drugs as potential ERα inhibitors in efforts to facilitate drug repurposing. This innovative stacked method is anticipated to facilitate community-wide efforts in efficiently narrowing down ER inhibitor screening.
... However, based on this qualitative analysis, it needs to be ascertained whether the sample added to the cell enters entirely and thoroughly into the cell. According to Yeap et al. (2021), MCF-7 cells have polygonal cell shapes with clear and distinctive cell membrane boundaries, while dead cells have distorted figures. This is different from the characteristics of living cells shown in the negative control (Fig. 6N1), so the addition of compound 2 indicates a cell response. ...
... Apoptosis and necrosis induction after 24 h of pyocyanin treatment (IC 50 ) of MCF-7 cells were assessed using Novocyte Flow Cytometer (Acea Biosciences, USA) as prescribed by [56]. In brief, harvested MCF-7 cells were washed and re-suspended in PBS (100 μL), followed by staining with the solution of Annexin V-FITC/PI (10 μl). ...
Background
Pyocyanin, a specific extracellular secondary metabolite pigment produced by Pseudomonas aeruginosa , exhibits redox activity and has toxic effects on mammalian cells, making it a new and potent alternative for treating cancer. Breast cancer (BC) treatment is now defied by acquired and de novo resistance to chemotherapy, radiation, or targeted therapies. Therefore, the anticancer activity of purified and characterized pyocyanin was examined against BC in our study.
Results
The maximum production of pyocyanin (53 µg/ml) was achieved by incubation of the highest pyocyanin-producing P. aeruginosa strain (P32) in pH-adjusted peptone water supplemented with 3% cetrimide under shaking conditions at 37 °C for 3 days. The high purity of the extracted pyocyanin was proven by HPLC against standard pyocyanin. The stability of pyocyanin was affected by the solvent in which it was stored. Therefore, the purified pyocyanin extract was lyophilized to increase its shelf-life up to one year. Using the MTT assay, we reported, for the first time, the cytotoxic effect of pyocyanin against human breast adenocarcinoma (MCF-7) with IC 50 = 15 μg/ml while it recorded a safe concentration against human peripheral blood mononuclear cells (PBMCs). The anticancer potential of pyocyanin against MCF-7 was associated with its apoptotic and necrotic activities which were confirmed qualitatively and quantitively using confocal laser scanning microscopy, inverted microscopy, and flow cytometry. Caspase-3 measurements, using real-time PCR and western blot, revealed that pyocyanin exerted its apoptotic activity against MCF-7 through caspase-3 activation.
Conclusion
Our work demonstrated that pyocyanin may be an ideal anticancer candidate, specific to cancer cells, for treating MCF-7 by its necrotic and caspase-3-dependent apoptotic activities.
... Moreover, curcumin has been shown to exert its functions through the regulation of miR expression. In breast cancer, it acts by upregulating miR-34a [83], miR-132 and miR-502c [84], miR-181b, miR-34a, miR-16, miR-15a, and miR-146b-5p, and by downregulating miR-19a and miR-19b [85], while in recent studies several other miRs were added to the list, either involving curcumin or its synthetic analogs [86][87][88]. In gastric cancer cells, similarly to breast cancer, curcumin enhances miR-34a expression [89] but inhibits miR-21 [90], which has also been reported in other cancer types (see below); in lung cancer it downregulates miR-186 [91] and circ-PRKCA [92] but upregulates miR-142-5p [93], miR-206 [94], and miR-192-5p [95]; in chronic myelogenous leukemia curcumin induces the miR-21-mediated modulation of the PTEN/AKT pathway, causing the inhibition of leukemic cell growth, both in vitro and in vivo [96], while in acute myeloid leukemia it inhibits the expression of the lncRNA HOTAIR and enhances the expression of miR-20a-5p [97]; in multiple myeloma it upregulates miR-101, thereby inhibiting EZH2 expression [98]; in colon cancer it downregulates both miR-130a [99] and miR-491 [100] but upregulates miR-137 [101], miR-200c [102], and miR-409-3p [103]; in melanoma it enhances the expression of miR-222-3p [104]; in pancreas cancer cells curcumin downregulates miR-199a and upregulates miR-22 [105]; in human prostate cancer stem cells, curcumin influences the expression of both miR-143 and miR-145 [106,107], and similarly to breast and gastric cancer it upregulates miR-34a [108]; in ovarian cancer, a curcumin derivative (ST09) deregulated the miR-199a-5p/DDR1 axis [109], while curcumin itself upregulates the lncRNA circ-PLEKHM3, promoting the intracellular depletion of miR-320a and suppressing cell proliferation and enhancing apoptosis [110]; in hepatocellular carcinoma it downregulates the expression of circ_0078710 (and consequently enhances miR-378b expression) [111] and downregulates miR-21-5p [112] and miR-21 [113]; in renal carcinoma, curcumin acts on the circ-FNDC3B/miR-138-5p/IGF2 axis [114]; in lymphoma, miR-28-5p is upregulated by curcumin treatment [115] while miR-21 is repressed [116]; in nasopharyngeal carcinoma, curcumin regulates the circRNA_102115/miR-335-3p/MAPK1 pathway [117], and other circRNAs have been identified as well [118]; in osteosarcoma it downregulates miR-21 [119]; in glioma, curcumin regulates the intracellular amounts of both the lncRNA H19 and miR-675 [120]; in bladder cancer it downregulates miR-1246 [121]. ...
Although the first discovery of a non-coding RNA (ncRNA) dates back to 1958, only in recent years has the complexity of the transcriptome started to be elucidated. However, its components are still under investigation and their identification is one of the challenges that scientists are presently facing. In addition, their function is still far from being fully understood. The non-coding portion of the genome is indeed the largest, both quantitatively and qualitatively. A large fraction of these ncRNAs have a regulatory role either in coding mRNAs or in other ncRNAs, creating an intracellular network of crossed interactions (competing endogenous RNA networks, or ceRNET) that fine-tune the gene expression in both health and disease. The alteration of the equilibrium among such interactions can be enough to cause a transition from health to disease, but the opposite is equally true, leading to the possibility of intervening based on these mechanisms to cure human conditions. In this review, we summarize the present knowledge on these mechanisms, illustrating how they can be used for disease treatment, the current challenges and pitfalls, and the roles of environmental and lifestyle-related contributing factors, in addition to the ethical, legal, and social issues arising from their (improper) use.
Transplant-associated thrombotic microangiopathy (TA-TMA) is an endotheliopathy complicating up to 30% of allogeneic hematopoietic stem cell transplants (alloHSCT). Positive feedback loops among complement, pro-inflammatory, pro-apoptotic, and coagulation cascades likely assume dominant roles at different disease stages. We hypothesized that mannose-binding lectin associated serine protease 2 (MASP2), principal activator of the lectin complement system, is involved in the microvascular endothelial cell (MVEC) injury characteristic of TA-TMA through pathways that are susceptible to suppression by anti-MASP2 monoclonal antibody narsoplimab. Pre-treatment plasmas from 8 of 9 TA-TMA patients achieving a complete TMA response in a narsoplimab clinical trial activated caspase 8, the initial step in apoptotic injury, in human MVEC. This was reduced to control levels following narsoplimab treatment in 7 of the 8 subjects. Plasmas from 8 individuals in an observational TA-TMA study, but not 8 alloHSCT subjects without TMA, similarly activated caspase 8, which was blocked in vitro by narsoplimab. mRNA sequencing of MVEC exposed to TA-TMA or control plasmas with and without narsoplimab suggested potential mechanisms of action. The top 40 narsoplimab-affected transcripts included upregulation of: SerpinB2, which blocks apoptosis by inactivating procaspase 3; CHAC1, which inhibits apoptosis in association with mitigation of oxidative stress responses; and pro-angiogenesis proteins TM4SF18, ASPM, and ESM1. Narsoplimab also suppressed transcripts encoding pro-apoptotic and pro-inflammatory proteins ZNF521, IL1R1, Fibulin-5, aggrecan, SLC14A1, and LOX1, and TMEM204, which disrupts vascular integrity. Our data suggest benefits to narsoplimab use in high-risk TA-TMA and provide a potential mechanistic basis for the clinical efficacy of narsoplimab in this disorder.
Curcumin is a potential plant‐derived drug for the treatment of breast cancer. Poor solubility and bioavailability are the main factors that limit its clinical application. Various structural modification strategies have been developed to improve the anti‐breast cancer activity of curcumin. This review focuses on the difference of modification sites and heterocyclic/non‐heterocyclic modifications to systematically summarize curcumin derivatives with better anti‐breast cancer activity.
Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.
The pathophysiology of endometriosis remains poorly understood. The aim of the present study was to investigate functions and pathways associated with the various miRNAs differentially expressed in patients with endometriosis. Plasma samples of the 200 patients from the prospective “ENDO-miRNA” study were analyzed and all known human miRNAs were sequenced. For each miRNA, sensitivity, specificity, and ROC AUC values were calculated for the diagnosis of endometriosis. miRNAs with an AUC ≥ 0.6 were selected for further analysis. A comprehensive review of recent articles from the PubMed, Clinical Trials.gov, Cochrane Library, and Web of Science databases was performed to identify functions and pathways associated with the selected miRNAs. In total, 2633 miRNAs were found in the patients with endometriosis. Among the 57 miRNAs with an AUC ≥ 0.6: 20 had never been reported before; one (miR-124-3p) had previously been observed in endometriosis; and the remaining 36 had been reported in benign and malignant disorders. miR-124-3p is involved in ectopic endometrial cell proliferation and invasion and plays a role in the following pathways: mTOR, STAT3, PI3K/Akt, NF-κB, ERK, PLGF-ROS, FGF2-FGFR, MAPK, GSK3B/β–catenin. Most of the remaining 36 miRNAs are involved in carcinogenesis through cell proliferation, apoptosis, and invasion. The three main pathways involved are Wnt/β–catenin, PI3K/Akt, and NF–KB. Our results provide evidence of the relation between the miRNA profiles of patients with endometriosis and various signaling pathways implicated in its pathophysiology.
