Human Cell Line MCF-7 Research Articles

Anti-tumor effects of low-dose metronomic vinorelbine in combination with alpelisib in breast cancer cells.

In metastatic breast cancer (MBC), PIK3CA mutations, activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway seem to be associated with chemotherapy resistance and poor outcome. Inhibition of the PI3K signaling pathway may lead to sensitization and prevention of the development of resistance to cytotoxic drugs. The present study aimed to investigate the anti-tumor activity of low-dose vinorelbine (VRL) combined with alpelisib, an α-selective PI3K inhibitor and degrader, in breast cancer (BC) cells. Human BC cell lines MCF-7, T-47D [both hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated], MDA-MB-231 and BT-549 (both triple-negative, wild-type PIK3CA) were exposed to a combination of low-dose VRL and alpelisib for 3 and 7 days. Cell viability was detected by the Alamar blue assay, and cell proliferation was determined by the BrdU incorporation. The effect of the substances on the p110α protein expression that is encoded by PIK3CA gene was investigated by Western blot. Low-dose VRL plus alpelisib showed synergistic anti-tumor effects and significantly inhibited cell viability and proliferation of MCF-7 and T-47D cells. Even lower alpelisib concentrations (10 ng/ml and 100 ng/ml) combined with low-dose metronomic VRL led to a significant reduction of cell viability of PIK3CA-mutated cells, and the anti-tumor activity was comparable with the effects at 1000 ng/ml alpelisib. Cell viability and proliferation of MDA-MB-231 and BT-549 cells were inhibited by VRL but not by alpelisib alone. This indicates that alpelisib did not significantly affect the cell growth of triple-negative, PIK3CA wild-type BC cells. The p110α expression was downregulated or not affected in PIK3CA-mutated cell lines, and not significantly upregulated in PIK3CA wild-type cell lines. In conclusion, combination of low-dose metronomic VRL and alpelisib showed synergistic anti-tumor effects and significantly inhibited the growth of HR-positive, HER2-negative, PIK3CA-mutated BC cells, providing a rationale for further efforts to evaluate this combination in vivo.

Enhanced Anticarcinogenic and Antimicrobial Response of Synthesized Tungsten Oxide Nanoparticles

In the present study, we fabricated tungsten trioxide nanoparticles (WO3 NPs) from a tungsten complex [W(C13H10NO)3] of ligand N-salicylideneaniline with tungstic acid as the precursor. Nanoparticles were synthesized using the direct thermal decomposition method. These nanoparticles were evaluated for cytotoxicity influence on human breast cancer MCF7 cell line (adenocarcinoma). The observed results suggested that WO3 can destroy 50 % of viable cells after 24 h of incubation at 37 °C. Based on these results, we concluded that WO3 nanoparticles could be a potential drug carrier candidate against human breast cancer cells based on the amount of the drug. In addition, WO3 nanoparticles exhibited significant antimicrobial and antifungal activity.

Modulation Effect on Tubulin Polymerization, Cytotoxicity and Antioxidant Activity of 1H-Benzimidazole-2-Yl Hydrazones

1H-benzimidazol-2-yl hydrazones with varying hydroxy and methoxy phenyl moieties were designed. Their effect on tubulin polymerization was evaluated in vitro on porcine tubulin. The compounds elongated the nucleation phase and slowed down the tubulin polymerization comparably to nocodazole. The possible binding modes of the hydrazones with tubulin were explored by molecular docking at the colchicine binding site. The anticancer activity was evaluated against human malignant cell lines MCF-7 and AR-230, as well as against normal fibroblast cells 3T3 and CCL-1. The compounds demonstrated a marked antineoplastic activity in low micromolar concentrations in both screened in vitro tumor models. The most active were the trimethoxy substituted derivative 1i and the positional isomers 1j and 1k, containing hydroxy and methoxy substituents: they showed IC50 similar to the reference podophyllotoxin in both tumor cell lines, accompanied with high selectivity towards the malignantly transformed cells. The compounds exerted moderate to high ability to scavenge peroxyl radicals and certain derivatives-1l containing metha-hydroxy and para-methoxy group, and 1b-e with di/trihydroxy phenyl moiety, revealed HORAC values high or comparable to those of well-known phenolic antioxidants. Thus the 1H-benisimidazol-2-yl hydrazones with hydroxy/methoxy phenyl fragments were recognized as new agents exhibiting promising combined antioxidant and antineoplastic action.

Synthesis, Anticancer Activity and Molecular Docking Studies of Hybrid Molecules Containing Indole‐Thiazolidinedione‐Triazole Moieties

AbstractA library of twelve hybrid molecules containing Indole‐Thiazolidinedione‐Triazole moieties were synthesized by following a series of N‐benzylation, Knoevenagel condensation and click chemistry reactions. The structure of novel molecules confirmed by spectral analysis data of 1H‐NMR, 13C‐NMR and LC–MS. All the compounds screened for their anticancer activity against the human liver cancer HePG‐2, human colorectal cancer HCT‐116, human prostate cancer PC‐3, and human breast cancer MCF7 cell lines. MTT assay protocol was employed and calculated IC50 value of all compounds. Doxorubicin was used as standard drug. m‐acetylphenyl substituted compound 9 i specified outstanding activity against four cell lines compared to doxorubicin. The p‐acetylphenyl and p‐nitrophenyl substituted compounds showed moderate activity against the same. Molecular docking studies were performed on EGFR, CDK2 and sorcin using Autodock Vina of PyRx tool. The binding energies and interactions acquired from docking results of compounds supported the investigational data.

Dual-Activated Nano-Prodrug for Chemo-Photodynamic Combination Therapy of Breast Cancer.

Herein, we developed a dual-activated prodrug, BTC, that contains three functional components: a glutathione (GSH)-responsive BODIPY-based photosensitizer with a photoinduced electron transfer (PET) effect between BODIPY and the 2,4-dinitrobenzenesulfonate (DNBS) group, and an ROS-responsive thioketal linker connecting BODIPY and the chemotherapeutic agent camptothecin (CPT). Interestingly, CPT displayed low toxicity because the active site of CPT was modified by the BODIPY-based macrocycle. Additionally, BTC was encapsulated with the amphiphilic polymer DSPE-mPEG2000 to improve drug solubility and tumor selectivity. The resulting nano-prodrug passively targeted tumor cells through enhanced permeability and retention (EPR) effects, and then the photosensitizing ability of the BODIPY dye was restored by removing the DNBS group with the high concentration of GSH in tumor cells. Light-triggered ROS from activated BODIPY can not only induce apoptosis or necrosis of tumor cells but also sever the thioketal linker to release CPT, achieving the combination treatment of selective photodynamic therapy and chemotherapy. The antitumor activity of the prodrug has been demonstrated in mouse mammary carcinoma 4T1 and human breast cancer MCF-7 cell lines and 4T1 tumor-bearing mice.

Evaluation of antimicrobial activity of thiolated methylated N-(4-N,N-dimethylaminobenzyl) chitosan as a new derivative of chitosan

Despite chitosan, a natural cationic polysaccharide derived from chitin, being applied as an antimicrobial agent, many studies are being performed for enhancing its capability to fight against pathogens. The aim of this study was to investigate the antibacterial effect of thiolated methylated N-(4-N,N-dimethylaminobenzyl) chitosan (TTMAC) polymer and its nanoparticles as a novel derivation of chitosan. The polymer derivative was synthetized and characterized via 1 H NMR, Fourier transform infrared and the Elman test. The nanoparticles with different N/P ratios were prepared by the ionic gelation method and were characterized by dynamic light scattering and transmission electron microscopy. The cellular toxicity of polymer and nanoparticles at different concentrations were evaluated on human MCF-7 cell line. Antimicrobial assay was performed on Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 25923) and Candida albicans (ATCC 10231) as Gram-negative, Gram-positive and yeast pathogens, respectively. The obtained results have shown the TTMAC polymer has a higher inhibition activity against microbial pathogens and also lower cellular toxicity in comparison with chitosan polymer. Furthermore, chitosan nanoparticles in comparison with TTMAC nanoparticles have lower size and highest zeta potential in different ratio and chitosan nanoparticles have more inhibitory effects against microbial pathogens. In conclusion, TTMAC derivative in polymeric form can be a promising tool against microbial pathogens.

Synthesis, Selective Cytotoxic Activity against Human Breast Cancer MCF7 Cell Line and Molecular Docking of Some Chalcone-Dihydropyrimidone Hybrids

Designed Chalcone-Dihydropyrimidinone hybrid compounds were synthesized expeditiously. The hybridization was performed through the Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) from the propargyloxy chalcones and azido-dihydropyrimidinones. The hybrid products were prepared in five steps with a 30–48% overall yield. Most of the compounds showed selective cytotoxicity and lower IC50 values (<10 µM) against MCF-7 (breast adenocarcinoma) cancer. Cytotoxicity was also observed against OVCAR-3 (ovary, adenocarcinoma), NCI/ADR-RES (ovary, multidrug-resistant adenocarcinoma), and U-251 (brain, glioblastoma) cell lines. The potency of the most active hybrids 9d, 9g, and 9h was greater than the individual parental compounds, suggesting the effectiveness of molecular hybridization on the cytotoxicity. Compounds 9d, 9g, and especially 9h showed high selectivity for breast cancer cells (MCF-7) regarding human keratinocytes (HaCaT). Molecular docking calculations for the 9d, 9g, and 9h hybrids in the active site of estrogen supported the hypothesis that the compounds act as ER-α antagonists, disrupting the cell proliferation process of MCF-7, corroborating the potency and selectivity observed for this tumoral cell line.

Anticancer effect of Illicium verum (star anise fruit) against human breast cancer MCF-7 cell line.

To investigate the anticancer effect of Illicium verum against human breast cancer MCF-7 cell line. An experimental study was conducted in Multidisciplinary and Tissue Culture Laboratory, Aga Khan University in collaboration with Pharmacology Department of Bahria University Medical and Dental College, Karachi, Pakistan from January 2021 to June 2021. MCF-7 cells of Luminal-A breast cancer were seeded in 96-well plate and treated with I.verum methanol extract. After incubation, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) dye was used for cell viability and cell proliferation assays to determine the number of dead and viable cells, and the absorbance was measured using an enzyme-linked immunosorbent assay (ELISA) plate reader. In cell viability assay, different doses of I. verum methanol extract were used to treat the MCF-7 (0.25, 0.5, 1, 3, 6, 12, 25, and 50μg/ml) cells. For apoptosis analysis, the cells were processed with 4´, 6-diamidino-2-phenylindole fluorescent nuclear dye (DAPI) and were examined for fluorescence intensity and apoptotic cells. For cell proliferation assay and apoptosis the IC50 dose of 5.5μg/ml I. verum methanol extract was used. The MCF-7 cells showed a significant reduction (p-value <0.01) in cell viability in the presence of all tested doses of I. verum methanol extract, except for the dose of 0.25μg/ml. The IC50 dose 5.5μg/ml of same extract also showed a significant reduction (p-value <0.01) in cell proliferation and apoptosis induction in MCF-7 cells. Illicium verum methanol extract possesses very potent anticancer action against MCF-7 cells through cytotoxicity, reduction, and inhibition of cancer cells and by inducing apoptosis.

Isolation and cytotoxic activities of undescribed iridoid and xanthone glycosides from Centaurium erythraea Rafn. (Gentianaceae)

Centaurium erythraea Rafn. (Gentianaceae) is used in internal traditional therapy as an anthelmintic, hypotensive, antipyretic, and antidiabetic. It is used externally for the treatment of wounds. Ursolic acid, maslinic acid, secologanin, secologanin dimethyl acetal, centauroside A, erythraeaxanthone I, erythraeaxanthone II, and demethyleustomin were isolated from aerial parts of Centaurium erythraea and were identified using spectroscopic methods, including NMR and mass spectrometry. The cytotoxic potency of undescribed compounds was evaluated by the XTT assay against human breast cancer MCF-7, MDA-MB-453 and mouse fibroblast 3T3-L1 cell lines. Erythraeaxanthone II was found to have the most potent cytotoxic activity.

Sesquiterpenoids and sesquiterpenoid dimers from the stem bark of Dysoxylum parasiticum (osbeck) kosterm

Two undescribed sesquiterpenoids, namely dysoticans A and B, and three undescribed sesquiterpenoid dimers, namely dysoticans C-E, together with six analogs, were isolated from the stem bark of Dysoxylum parasiticum (Osbeck) Kosterm. (Meliaceae), growing in West Java, Indonesia. Their structures were elucidated based on extensive spectroscopic analysis and theoretical simulations of ECD spectra and 13C NMR shifts. Dysoticans A and B possessed undescribed cadinanes with minor modifications, while C and D featured unprecedented pseudo-sesquiterpenoid dimers through O-ether linkages of cadinanes and guaianes, respectively. Dysotican E was also characterized as the true-sesquiterpenoid dimer featuring eudesmane-germacrene hybrid framework from the Meliaceae family. Furthermore, A-C and E showed moderate activities against the human breast cancer MCF-7 and cervical cancer HeLa cell lines with IC50 values ranging from 22.15 to 45.14 μM. D selectively exhibited significant cytotoxicity against the HeLa cell line with an IC50 value of 13.00 ± 0.13 μM.

Feeding a High-Fat Diet for a Limited Duration Increases Cancer Incidence in a Breast Cancer Model

High-fat intake by young Asian women impacts the risk of breast cancer. Understanding the underlying molecular mechanisms may be essential for disease prevention in Asia as well as globally. We aimed to examine the effects of corn oil- and animal fat-based high-fat diets (32.9 and 31.4%, respectively, of fat energy ratio as compared to 12.3% in the standard diet) on mammary carcinogenesis and alterations in gene expression and epigenetic statuses in the mammary gland during the growth stages in a rat model. An increased incidence of carcinomas was observed after the cessation of high-fat feeding. In addition, rapid tumor growth and elevations in Celsr2 expression, which may be a result of DNA hypomethylation patterns in the 3′ untranslated region of the gene were noted in the animal fat group. In the human breast carcinoma cell line MCF7, a marginal decrease in cell viability was observed following the knockdown of Celsr2, suggesting that the animal fat-associated risk of cancer is partly due to the deregulation of mammary cell proliferation via non-metabolic gene functions. The present results will contribute to the development of strategies for controlling the food-associated risk of breast cancer, particularly in younger age groups.

Design, synthesis and molecular modeling study of certain quinazolinone derivatives targeting poly (ADP-ribose) polymerase 1 (PARP-1) enzyme as anti-breast cancer and radio-sensitizers

A novel two series of S-alkylated quinazolinones 4–10 and N-alkylated quinazolinones 11–17 was designed and synthesized as potential PARP-1 inhibitors. Quinazolinone scaffold was used as a bioisostere to the phthalazinone core of Olaparib (reference drug). All the newly synthesized compounds were evaluated for their in vitro cytotoxicity against the human breast cancer MCF-7 cell line. The most active compounds, 10 and 15, with IC50 values of 11.4 µM and 10.6 µM, respectively, which are 2.8 and 3 times higher than Doxorubicin (IC50 32.02 µM), were tested for PARP-1 inhibitory activity and showed IC50 0.17 µM and 0.14 µM, respectively when compared to Olaparib (IC50 0.06 µM). Additionally, the capability of γ-radiation to augment the in vitro cytotoxic activity of 10 and 15 was studied and exhibited an increase in the cell-killing effect at lower concentrations after combining with γ-radiation. A molecular modeling study was performed to investigate the possible binding mode of compounds 10 and 15 in the active site of the PARP-1 enzyme.

New Jatrophane-Type Diterpenoids from Euphorbia kansui as Potential MDR Reversal Agents.

A serial jatrophane-type diterpenoids, comprised with three undescribed compounds kanesulones C-E (1-3) and four known ones (4-7), were obtained from the roots of Euphorbia kansui. The structures of compounds 1-3 were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS, the absolute configuration of 1 was revealed by single crystal X-ray diffraction. These isolates were assayed for their multidrug resistance reversing activities on human breast adenocarcinoma cell line MCF-7/ADR. Compound 1 possessed potential as low toxic MDR modulator that could promote the efficacy of anticancer drug adriamycin ca. 85-fold at 5 μM, as 12 times stronger than the positive drug verapamil.

Design, combinatorial synthesis and cytotoxic activity of 2-substituted furo[2,3-d]pyrimidinone and pyrrolo[2,3-d]pyrimidinone library.

A facile protocol was developed for the combinatorial synthesis of furo[2,3-d]pyrimidinone and pyrrolo[2,3-d]pyrimidinone library via a one-pot condensation, from 2-amino furans/pyrroles. Herein reported process required a similar reaction condition, providing mild access to two diverse series of natural product-like heterocycles. Both furo[2,3-d]pyrimidinones and pyrrolo[2,3-d]pyrimidinones were evaluated in vitro against a panel of human cancer cell lines including against human cancer HeLa (cervical), MCF-7 (breast) and HT-29 (colon) cell lines. Derivative 12n ((2-(4-chlorophenyl)-1-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrrolo[2,3-d]pyrimidin-4(1H)-one)) showed high activity (IC50 = 6.55 ± 0.31µM) against the HeLa cell line. These products could be subjected to a various modification and therefore represent important skeletons for the anticancer drug discovery.

Benzo[&lt;i&gt;c&lt;/i&gt;]phenanthridine alkaloids and glycosylated flavonoids from the roots of &lt;i&gt;Zanthoxylum gilletii&lt;/i&gt; (Rutaceae)

The roots of &lt;i&gt;Zanthoxylum gilletii&lt;/i&gt; have been chemically investigated and led to the isolation and characterization of nine compounds including three benzo[&lt;i&gt;c&lt;/i&gt;]phenanthridine alkaloids oxychelerythrine (&lt;b&gt;1&lt;/b&gt;), angoline (&lt;b&gt;2&lt;/b&gt;) and arnottianamide (&lt;b&gt;3&lt;/b&gt;); two glycosylated flavonoids hesperidin (&lt;b&gt;4&lt;/b&gt;) and its analogue neohesperidin (&lt;b&gt;5&lt;/b&gt;) along with four common specialized metabolites including sesamin (&lt;b&gt;6&lt;/b&gt;), lupeol (&lt;b&gt;7&lt;/b&gt;), β-sitosterol (&lt;b&gt;8&lt;/b&gt;) and its derivative daucosterol (&lt;b&gt;9&lt;/b&gt;). Their structures were established based on their recorded 1D and 2D-NMR data. Some compounds (&lt;b&gt;1&lt;/b&gt;, &lt;b&gt;2&lt;/b&gt;, &lt;b&gt;3&lt;/b&gt;, &lt;b&gt;6&lt;/b&gt; and &lt;b&gt;7&lt;/b&gt;) did not display a cytotoxic activity until the highest concentration of 200 μM against the human cell lines MCF-7 and A549. The chemotaxonomic relevance of this study has been discussed. To the best of our knowledge, except for the five compounds &lt;b&gt;3&lt;/b&gt;, &lt;b&gt;6&lt;/b&gt;-&lt;b&gt;9&lt;/b&gt;, all the four others have been for the first time isolated from &lt;i&gt;Z. gilletii&lt;/i&gt; (Rutaceae).

Size-resolved counting of circulating tumor cells on pinched flow-based microfluidic cytometry.

Precise cell detecting and counting is meaningful in circulating tumor cells (CTCs) analysis. In this work, a simple cyclic olefin copolymer (COC) microflow cytometer device was developed for size-resolved CTCs counting. The proposed device is constructed by a counting channel and a pinched injection unit having three channels. Through injection flow rate control, microspheres/cells can be focused into the centerline of the counting channel. Polystyrene microspheres of 3, 9, 15, and 20µm were used for the microspheres focusing characterization. After coupling to laser-induced fluorescence detection technique, the proposed device was used for polystyrene microspheres counting and sizing. A count accuracy up to 97.6% was obtained for microspheres. Moreover, the proposed microflow cytometer was applied to CTCs detecting and counting. To mimic blood sample containing CTCs and CTCs mixture with different subtypes, an MDA-MB-231 (human breast cell line) spiked red blood cells sample and a mixture of MDA-MB-231 and MCF-7 (human breast cell line) sample were prepared, respectively, and then analyzed by the developed pinched flow-based microfluidic cytometry. The simple fabricated and easy operating COC microflow cytometer exhibits the potential in the point-of-care clinical application.

A High-Throughput Search for SFXN1 Physical Partners Led to the Identification of ATAD3, HSD10 and TIM50.

Simple SummaryMitochondria are central players in cell fate and cell death. Indeed, mitochondrial dysfunction has been observed in many diseases, including neurodegenerative diseases. The activity of these organelles relies on numerous mitochondrial transporters, among which the sideroflexins have received little attention to date despite their emerging importance in human health. To better understand the cellular functions of these transporters and their associations with diseases, we herein investigated the molecular partners of one human sideroflexin, SFXN1. Several proteins capable of interacting with SFXN1 were identified, including ATAD3 and HSD10, two mitochondrial proteins linked to neuronal disorders.Sideroflexins (SFXN, SLC56) are a family of evolutionarily conserved mitochondrial carriers potentially involved in iron homeostasis. One member of the SFXN family is SFXN1, recently identified as a human mitochondrial serine transporter. However, little is known about the SFXN1 interactome, necessitating a high-throughput search to better characterize SFXN1 mitochondrial functions. Via co-immunoprecipitation followed by shotgun mass spectrometry (coIP-MS), we identified 96 putative SFXN1 interactors in the MCF7 human cell line. Our in silico analysis of the SFXN1 interactome highlights biological processes linked to mitochondrial organization, electron transport chains and transmembrane transport. Among the potential physical partners, ATAD3A and 17β-HSD10, two proteins associated with neurological disorders, were confirmed using different human cell lines. Nevertheless, further work will be needed to investigate the significance of these interactions.

Development and In vitro characterization of pullulan fast dissolving films loaded with Panax ginseng extract, antioxidant properties and cytotoxic efficiency on lung and breast cancer cell lines

The objectives of the current research were to produce fast dissolving oral films (FDOFs) containing standardised freeze-dried ginseng root extract (FDG) and to exploit and evaluate the effect of pullulan on the fast-dissolving oral films to impart desirable features to the drug formulation, such as rapid drug release, high release rates and improve the active ingredients' stability. Pullulan was used as a film-forming polymer and propylene glycol as a plasticizer, and films were produced by a solvent-casting method. The FDOFs were evaluated for the physicomechanical properties such as disintegration, Young's modulus, tensile strength and elongation at the break. The interaction between the polymer and freeze-dried ginseng extract in the film formulation was determined by ATR-FTIR method. Morphological characteristics were identified by scanning electron microscopy. Along with the formulation study, its antioxidant capacity and anti-cancer effect on lung and breast cancer cell lines were also observed. In different antioxidant experiments (FRAP, CUPRAC, DPPH and ABTS), the total antioxidant content of FDG was observed to be between 3.379 and 11,216 mg/g extract. In the present study, we also tested FDG extract on human breast cancer model MCF-7 and human lung cancer model A549 cell lines in vitro. Based on MCF-7 and A549 cell viability results, FDG extract exerted cytotoxicity on both cancer lines in a dose-dependent manner. The results manifested that the FDOFs containing FDG had good physicomechanical properties and fast release profiles. The incorporation of the FDG into the films promoted reduction of the tensile strength and Young's modulus, and an increase in elongation compared to F1. The film exhibited maximal release in 10 min of the active compounds (Rb1 and RG2), and it was more than 97 ± 0.35%. The results may lay the groundwork for future studies, regarding the development of FDOFs as P. ginseng extract-based dosage forms, which might increase the pharmacological activity and multifunctional properties closer to the desired level and may be a useful and effective anticancer-containing product with future in vivo studies.

Synthesis, Anticancer Activities and Molecular Docking Studies of a Novel Class of 2-Phenyl-5,6,7,8-tetrahydroimidazo [1,2-b]pyridazine Derivatives Bearing Sulfonamides.

In the present study, new 2-phenyl-5,6,7,8-tetrahydroimidazo [1,2-b]pyridazines bearing sulfonamides were synthesized, characterized and evaluated for their anticancer activities. The structures of these derivatives were elucidated by 1H NMR, 13C NMR, infrared and high-resolution mass spectrometry for further validation of the target compound structures. The anticancer activities of the new molecules were evaluated against five human cancer cell lines, including A-549, Hs-683, MCF-7, SK-MEL-28 and B16-F10 cell lines using 5-fluorouracil and etoposide as the reference drugs. Among the tested compounds, 4e and 4f exhibited excellent activities in the same range of the positive controls, 5-fluorouracil and etoposide, against MCF-7 and SK-MEL-28 cancer cell lines, with IC50 values ranging from 1 to 10 μM. The molecular docking studies of 4e and 4f showed a strong binding with some kinases, which are linked to MCF-7 and SK-MEL-28 cancer cell lines.

Cromolyn chitosan nanoparticles reverse the DNA methylation of RASSF1A and p16 genes and mitigate DNMT1 and METTL3 expression in breast cancer cell line and tumor xenograft model in mice

BackgroundDeveloping epigenetic drugs for breast cancer (BC) remains a novel therapeutic approach. Cromolyn is a mast cell stabilizer emerging as an anticancer drug; its encapsulation in chitosan nanoparticles (CSNPs) improves its effect and bioavailability. However, its effect on DNA and RNA methylation machineries has not been previously tackled. MethodsThe possible anticancer effect of cromolyn CSNPs and its potential as an epigenetic drug was investigated in vitro using MCF-7 human BC cell line and in vivo using Ehrlich ascites carcinoma-xenograft model in mice symbolizing murine mammary adenocarcinoma. Mice were injected with a single dose of Ehrlich ascites carcinoma cells subcutaneously for the induction of tumor mass, and then randomized into three groups: control, cromolyn CSNPs (equivalent to 5 mg cromolyn/kg, i.p.) and plain CSNPs twice/week for 2 weeks. ResultsCromolyn CSNPs showed prominent anticancer effect in MCF-7 cells by reducing the cell viability percent and enhancing DNA damage in the comet assay demonstrating its apoptotic actions. Mechanistically, cromolyn CSNPs influenced potential epigenetic processes through mitigating DNA methyltransferase 1 (DNMT1) expression, reversing the hypermethylation pattern of the tumor suppressor RASSF1A and p16 genes and attenuating the expression of the RNA N6-methyladenosine writer, methyltransferase-like 3 (METTL3). Cromolyn CSNPs diminished ERK1/2 phosphorylation, a possible arm influencing DNMT1 expression. In vivo, cromolyn CSNPs lessened the tumor volume and halted DNMT1 and METTL3 expression in Ehrlich carcinoma mice. ConclusionsCromolyn CSNPs have the premise as an epigenetic drug through inhibiting ERK1/2 phosphorylation/DNMT1/DNA methylation and possibly impacting the RNA methylation machinery via mitigating METTL3 expression.