-
Biomedicine & Pharmacotherapy =... Jun 2024The development of new anticancer agents is one of the most urgent topics in drug discovery. Inhibition of molecular chaperone Hsp90 stands out as an approach that...
The development of new anticancer agents is one of the most urgent topics in drug discovery. Inhibition of molecular chaperone Hsp90 stands out as an approach that affects various oncogenic proteins in different types of cancer. These proteins rely on Hsp90 to obtain their functional structure, and thus Hsp90 is indirectly involved in the pathophysiology of cancer. However, the most studied ATP-competitive inhibition of Hsp90 at the N-terminal domain has proven to be largely unsuccessful clinically. Therefore, research has shifted towards Hsp90 C-terminal domain (CTD) inhibitors, which are also the focus of this study. Our recent discovery of compound C has provided us with a starting point for exploring the structure-activity relationship and optimising this new class of triazole-based Hsp90 inhibitors. This investigation has ultimately led to a library of 33 analogues of C that have suitable physicochemical properties and several inhibit the growth of different cancer types in the low micromolar range. Inhibition of Hsp90 was confirmed by biophysical and cellular assays and the binding epitopes of selected inhibitors were studied by STD NMR. Furthermore, the most promising Hsp90 CTD inhibitor 5x was shown to induce apoptosis in breast cancer (MCF-7) and Ewing sarcoma (SK-N-MC) cells while inducing cause cell cycle arrest in MCF-7 cells. In MCF-7 cells, it caused a decrease in the levels of ERα and IGF1R, known Hsp90 client proteins. Finally, 5x was tested in zebrafish larvae xenografted with SK-N-MC tumour cells, where it limited tumour growth with no obvious adverse effects on normal zebrafish development.
PubMed: 38889640
DOI: 10.1016/j.biopha.2024.116941 -
Frontiers in Chemistry 2024This study focused on developing new inhibitors for the MCF-7 cell line to contribute to our understanding of breast cancer biology and various experimental techniques....
This study focused on developing new inhibitors for the MCF-7 cell line to contribute to our understanding of breast cancer biology and various experimental techniques. 3D QSAR modeling was used to design new tetrahydrobenzo[4, 5]thieno[2, 3-d]pyrimidine derivatives with good characteristics. Two robust 3D-QSAR models were developed, and their predictive capacities were confirmed through high correlations [CoMFA (Q = 0.62, = 0.90) and CoMSIA (Q = 0.71, = 0.88)] via external validations (R = 0.90 and R = 0.91, respectively). These successful evaluations confirm the potential of the models to provide reliable predictions. Six candidate inhibitors were discovered, and two new inhibitors were developed using computational methods. The ADME-Tox properties and pharmacokinetic characteristics of the new derivatives were evaluated carefully. The interactions between the new tetrahydrobenzo[4, 5]thieno[2, 3-d]pyrimidine derivatives and the protein ERα (PDB code: 4XO6) were highlighted by molecular docking. Additionally, MM/GBSA calculations and molecular dynamics simulations provided interesting information on the binding stabilities between the complexes. The pharmaceutical characteristics, interactions with protein, and stabilities of the inhibitors were examined using various methods, including molecular docking and molecular dynamics simulations over 100 ns, binding free energy calculations, and ADME-Tox predictions, and compared with the FDA-approved drug capivasertib. The findings indicate that the inhibitors exhibit significant binding affinities, robust stabilities, and desirable pharmaceutical characteristics. These newly developed compounds, which act as inhibitors to mitigate breast cancer, therefore possess considerable potential as prospective drug candidates.
PubMed: 38887699
DOI: 10.3389/fchem.2024.1384832 -
BMC Genomics Jun 2024A growing number of studies have demonstrated that the polar regions have the potential to be a significant repository of microbial resources and a potential source of...
BACKGROUND
A growing number of studies have demonstrated that the polar regions have the potential to be a significant repository of microbial resources and a potential source of active ingredients. Genome mining strategy plays a key role in the discovery of bioactive secondary metabolites (SMs) from microorganisms. This work highlighted deciphering the biosynthetic potential of an Arctic marine-derived strain Aspergillus sydowii MNP-2 by a combination of whole genome analysis and antiSMASH as well as feature-based molecular networking (MN) in the Global Natural Products Social Molecular Networking (GNPS).
RESULTS
In this study, a high-quality whole genome sequence of an Arctic marine strain MNP-2, with a size of 34.9 Mb was successfully obtained. Its total number of genes predicted by BRAKER software was 13,218, and that of non-coding RNAs (rRNA, sRNA, snRNA, and tRNA) predicted by using INFERNAL software was 204. AntiSMASH results indicated that strain MNP-2 harbors 56 biosynthetic gene clusters (BGCs), including 18 NRPS/NRPS-like gene clusters, 10 PKS/PKS-like gene clusters, 8 terpene synthse gene clusters, 5 indole synthase gene clusters, 10 hybrid gene clusters, and 5 fungal-RiPP gene clusters. Metabolic analyses of strain MNP-2 grown on various media using GNPS networking revealed its great potential for the biosynthesis of bioactive SMs containing a variety of heterocyclic and bridge-ring structures. For example, compound G-8 exhibited a potent anti-HIV effect with an IC value of 7.2 nM and an EC value of 0.9 nM. Compound G-6 had excellent in vitro cytotoxicities against the K562, MCF-7, Hela, DU145, U1975, SGC-7901, A549, MOLT-4, and HL60 cell lines, with IC values ranging from 0.10 to 3.3 µM, and showed significant anti-viral (H1N1 and H3N2) activities with IC values of 15.9 and 30.0 µM, respectively.
CONCLUSIONS
These findings definitely improve our knowledge about the molecular biology of genus A. sydowii and would effectively unveil the biosynthetic potential of strain MNP-2 using genomics and metabolomics techniques.
Topics: Aspergillus; Arctic Regions; Humans; Multigene Family; Biological Products; Aquatic Organisms; Cell Line, Tumor; Biosynthetic Pathways; Secondary Metabolism; Genome, Fungal
PubMed: 38886660
DOI: 10.1186/s12864-024-10501-0 -
Cancer Reports (Hoboken, N.J.) Jun 2024It has been reported that long non-coding RNAs (lncRNAs) can play important roles in a variety of biological processes and cancer regulatory networks, including breast...
BACKGROUND
It has been reported that long non-coding RNAs (lncRNAs) can play important roles in a variety of biological processes and cancer regulatory networks, including breast cancer.
AIMS
This study aimed to identify a novel upregulated lncRNA in breast cancer and its associated gene using bioinformatics analysis, and then evaluate their potential roles in breast cancer.
METHODS AND RESULTS
Extensive in silico studies were performed using various bioinformatics databases and tools to identify a potential upregulated breast cancer-associated lncRNA and its co-expressed gene, and to predict their potential roles, functions, and interactions. The expression level of MRPS30-DT lncRNA and MRPS30 was assessed in both BC tissues and cell lines using qRT-PCR technology. MRPS30-DT lncRNA and MRPS30 were selected as target genes using bioinformatics analysis. We found that MRPS30-DT and MRPS30 were significantly overexpressed in BC tissues compared with normal tissues. Also, MRPS30 showed upregulation in all three BC cell lines compared with HDF. On the other hand, MRPS30-DT significantly increased in MDA-MB-231 compared with HDF. While the expression of MRPS30-DT was significantly dropped in the resistance cell line MCF/MX compared to HDF and MCF7. Moreover, bioinformatics analysis suggested that MRPS30-DT and MRPS30 may play a potential role in BC through their involvement in some cancer signaling pathways and processes, as well as through their interaction with TFs, genes, miRNAs, and proteins related to carcinogenesis.
CONCLUSIONS
Overall, our findings showed the dysregulation of MRPS30-DT lncRNA and MRPS30 may provide clues for exploring new therapeutic targets or molecular biomarkers in BC.
Topics: Humans; RNA, Long Noncoding; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Computational Biology; Computer Simulation; Cell Line, Tumor; Biomarkers, Tumor; Up-Regulation; Cell Proliferation; MCF-7 Cells; Gene Regulatory Networks
PubMed: 38886335
DOI: 10.1002/cnr2.2114 -
ACS Omega Jun 2024The utilization of metallodrugs as a viable alternative to organic molecules has gained significant attention in modern medicine. We hereby report synthesis of new imine...
The utilization of metallodrugs as a viable alternative to organic molecules has gained significant attention in modern medicine. We hereby report synthesis of new imine quinoline ligand ()-based Cu(II) complexes and evaluation of their potential biological applications. Syntheses of the ligand and complexes were achieved by condensation of 7-chloro-2-hydroxyquinoline-3-carbaldehyde and 2,2'-thiodianiline, followed by complexation with Cu(II) metal ions. The synthesized ligand and complexes were characterized using UV-vis spectroscopy, TGA/DTA, FTIR spectroscopy, H and C NMR spectroscopy, and pXRD. The pXRD diffractogram analysis revealed that the synthesized ligand and its complexes were polycrystalline systems, with nanolevel average crystallite sizes of 13.28, 31.47, and 11.57 nm for , , and , respectively. The molar conductivity confirmed the nonelectrolyte nature of the Cu(II) complexes. The biological activity of the synthesized ligand and its Cu(II) complexes was evaluated with assays, to examine anticancer activity against the human breast cancer cell line and antibacterial activity against Gram-positive () and Gram-negative ( and ) bacterial strains. The complex had the highest cytotoxic potency against breast cancer cells, with an IC of 43.82 ± 2.351 μg/mL. At 100 μg/mL, induced the largest reduction of cancer cell proliferation by 97%, whereas reduced cell proliferation by 53% and by 28%. The minimum inhibitory concentration for was found to be 12.5 μg/mL against the three tested pathogens. Evaluation of antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl revealed that exhibited the highest antioxidant activity with IC of 153.3 ± 1.02 μg/mL. Molecular docking results showed strong binding affinities of to active sites of , , and , indicating its high biological activity compared to and .
PubMed: 38882155
DOI: 10.1021/acsomega.4c02129 -
ACS Omega Jun 2024In the present study, we have synthesized a zinc sulfide/chitosan (ZS/CS) nanocomposite by utilizing simple, economical, and environmentally friendly methods. The...
Facile Synthesis of a Crystalline Zinc Sulfide/Chitosan Biopolymer Nanocomposite: Characterization and Application for Photocatalytic Degradation of Textile Dyes and Anticancer Activity.
In the present study, we have synthesized a zinc sulfide/chitosan (ZS/CS) nanocomposite by utilizing simple, economical, and environmentally friendly methods. The synthesized nanomaterials were characterized by different analytical techniques such as XRD, FE-SEM, EDS, and FTIR to determine the phase structure, morphology, and elemental composition. FTIR spectroscopy was used to confirm the functional groups of the synthesized zinc sulfide (ZS) nanoparticles and ZS/CS composite. Besides, the optical properties of the as-synthesized nanocomposite was analyzed by a UV-visible spectrophotometer, and the estimated band gap energy is ∼3.03 eV. The photocatalytic efficiency of the synthesized ZS/CS nanocomposite was investigated against two textile dyes, Crystal Violet (CV) and Acid Red-I (AR-I), under UV-visible light irradiation. The nanocomposite showed excellent photocatalytic activity against the dyes, and photodegradation was estimated to be about 93.44 and 90.67% for CV and AR-I, respectively. The nanocomposite was reused for three consecutive cycles. The results revealed that the photocatalyst displayed good reusability during the photocatalytic decomposition and thus is considered a cost-effective and promising photocatalyst in degrading dye pollutants. The kinetic study proved that the pseudo-first-order reaction kinetics was followed by the degradation process. We also examined the anticancer activity of ZS and ZS/CS against human breast and myelogenous leukemia cancer cell lines, namely, MCF-7 and K-562, and the half minimal inhibitory concentrations were found to be less than 50 μg/mL.
PubMed: 38882115
DOI: 10.1021/acsomega.4c00247 -
Translational Cancer Research May 2024Chidamide (CHI) is a subtype-selective histone deacetylase inhibitor (HDACI) developed in China and approved as a second-line treatment combined with the aromatase...
BACKGROUND
Chidamide (CHI) is a subtype-selective histone deacetylase inhibitor (HDACI) developed in China and approved as a second-line treatment combined with the aromatase inhibitor for hormone receptor-positive (HR)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. However, drug resistance is commonly occurred after a long period of medication. This study aimed to investigate the characterization of induced resistance to CHI and explore the potential cross-resistance to chemotherapeutic agents.
METHODS
CHI with gradually increasing concentrations was added to breast cancer MCF7 cells to establish a CHI-resistant MCF7 (MCF7-CHI-R) cell line. Cell counting kit-8 (CCK-8) assays were performed to detect half-maximal inhibitory concentration (IC) of CHI. Colony formation was used to determine the proliferation inhibition rate. Western blot analysis was conducted to detect expressions of protein related with cell cycle, apoptosis, ferroptosis, and histone deacetylase (HDAC). Flow cytometry was used to analyze apoptosis and cell cycle.
RESULTS
The IC value of CHI of MCF7-CHI-R cells was increased in comparison with MCF7 cells. And CHI led to cell cycle arrest and ferroptosis, which were not exhibited in MCF7-CHI-R cells. Moreover, HDAC activity decreased in MCF7-CHI-R cells in comparison with MCF7 cells, and HDAC1 and HDAC10 might be involved in the resistance to CHI. In addition, MCF7-CHI-R cells were resistant to gemcitabine (GEM), doxorubicin (ADM), docetaxel (DXT), albumin-bound paclitaxel (nab-PTX) and paclitaxel (PTX).
CONCLUSIONS
The MCF7-CHI-R was established and the anti-ferroptosis pathway activation was involved in the resistance of MCF-CHI-R cells. Also, MCF7-CHI-R cells were resistant to GEM, ADM, DXT, nab-PTX and PTX.
PubMed: 38881946
DOI: 10.21037/tcr-23-2169 -
Cell Death & Disease Jun 2024Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of...
Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca channel. This causes cytosolic Ca overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death which are reversed upon chelating Ca or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.
Topics: Humans; Tamoxifen; Breast Neoplasms; Ferroptosis; Female; RNA, Long Noncoding; Cyclic AMP; Calcium; Drug Resistance, Neoplasm; Cell Line, Tumor; Animals; Receptors, Estrogen; Mice; Reactive Oxygen Species; MCF-7 Cells
PubMed: 38879508
DOI: 10.1038/s41419-024-06814-3 -
Scientific Reports Jun 2024Antitumor drugs used today have shown significant efficacy and are derived from natural products such as plants. Iso-mukaadial acetate (IMA) has previously been shown to...
Antitumor drugs used today have shown significant efficacy and are derived from natural products such as plants. Iso-mukaadial acetate (IMA) has previously been shown to possess anticancer properties by inducing apoptosis. The purpose of this study was to investigate the therapeutic effect of IMA in the breast cancer xenograft mice model. Female athymic nude mice were used and inoculated with breast cancer cells subcutaneously. Untreated group one served as a negative control and positive control group two (cisplatin) was administered intravenously. IMA was administered orally to group three (100 mg/kg) and group four (300 mg/kg). Blood was collected (70 μL) from the tail vein on day zero, day one and day three. Tumor regression was measured every second day and body mass was recorded each day. Estimation of serum parameters for renal indices was examined using a creatinine assay. Histopathological analysis was conducted to evaluate morphological changes of liver, kidney, and spleen tissues before and after compound administration under a fluorescence light microscope. Histopathological analysis of tumors was conducted before and after compound administration. Apoptotic analysis using the TUNEL system was conducted on liver, kidney, and spleen tissues. Tumor shrinkage and reduction in body mass were observed after treatment with IMA. Serum creatinine was slightly elevated after treatment with IMA at a dosage of 100 and 300 mg/kg. Histopathological results of the liver exhibited no changes before and after IMA while the kidney and spleen tissues showed changes in the cellular structure. IMA showed no cytotoxic effect on the tumor cells, and cell proliferation was observed. Apoptotic assay stain with TUNEL showed apoptotic cells in spleen tissue and kidney but no apoptotic cells were observed in liver tissue section treated with IMA. IMA showed clinical toxic signs that resulted in the suffering and death of the mice immediately after IMA administration. Histopathology of tumor cells showed that IMA did not inhibit cell proliferation and no cellular damage was observed. Therefore, based on the results obtained, we cannot make any definitive conclusion on the complete effect of IMA in vivo. IMA is toxic, poorly soluble, and not safe to use in animal studies. The objective of the study was not achieved, and the hypothesis was rejected.
Topics: Animals; Humans; Female; Mice; Xenograft Model Antitumor Assays; Breast Neoplasms; Apoptosis; Mice, Nude; MCF-7 Cells; Antineoplastic Agents; Cell Proliferation
PubMed: 38877067
DOI: 10.1038/s41598-024-64474-x -
RSC Advances Jun 2024Herein we report the design and synthesis of a series of fully-substituted 4-(trifluoromethyl)isoxazoles and evaluation of their anti-cancer activities against MCF-7,...
Exploring the impact of trifluoromethyl (-CF) functional group on the anti-cancer activity of isoxazole-based molecules: design, synthesis, biological evaluation and molecular docking analysis.
Herein we report the design and synthesis of a series of fully-substituted 4-(trifluoromethyl)isoxazoles and evaluation of their anti-cancer activities against MCF-7, 4T1 and PC-3 cell lines as a proof of concept study. 4-(Trifluoromethyl)isoxazole is a synthetically challenging class of molecules and very few synthetic methods have been developed so far and all of them suffered from several serious limitations. Recently we developed a novel, metal-free, and general synthetic strategy to access synthetically challenging 4-(trifluoromethyl)isoxazoles starting from readily available chalcones using cheap CFSONa as the source of the -CF group and multitasking BuONO as an oxidant as well as the source of N and O and thus we have overcome the limitations of the previous methods. Based on the structure of an isoxazole-based anti-cancer agent, 3-(3,4-dimethoxyphenyl)-5-(thiophen-2-yl)isoxazole 14, we designed a set of 4-(trifluoromethyl)isoxazoles for synthesis and further anti-cancer evaluation. Among various molecules, 3-(3,4-dimethoxyphenyl)-5-(thiophen-2-yl)-4-(trifluoromethyl)isoxazole 2g (IC = 2.63 μM) and 3-(thiophen-2-yl)-5-(4-(thiophen-2-yl)-1-pyrrol-3-yl)-4-(trifluoromethyl)isoxazole 5 (IC = 3.09 μM) exhibited the best anti-cancer activity against the human breast cancer cell-lines (MCF-7), 2g being the lead molecule among all. Interestingly, 2g is found to be almost 8 times more active compared to its non-trifluoromethylated analogue, , 3-(3,4-dimethoxyphenyl)-5-(thiophen-2-yl)isoxazole 14 (IC = 19.72 μM) which revealed the importance of a 'CF' moiety in enhancing the anti-cancer activity of 14. Further studies such as apoptosis induction, cell cycle analysis, and nuclear staining revealed an apoptotic cell death mechanism. The molecular docking, induced fit analysis, and ADME studies further supported the effect of a -CF moiety on the enhancement of anti-cancer activity of isoxazole-based anti-cancer molecules. Further exploration of the biodistribution and therapeutic efficacy of lead 2g holds significant promise, positioning it as a potential candidate for anticancer therapy.
PubMed: 38873543
DOI: 10.1039/d4ra02856b