Leukemia K562 Cells Research Articles

MiR-302 Cluster Inhibits Angiogenesis and Growth of K562 Leukemia Cells by Targeting VEGFA [Retraction

[This retracts the article DOI: 10.2147/OTT.S190146.].

Tet2-mediated DNA demethylation regulates the proliferation and apoptosis of human leukemia K562 cells.

TET2 is a member of the TET protein family which is responsible for active DNA demethylation through catalyzing the successive oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), and mutations of Tet2 frequently lead to hematological malignancies. However, the relationship between Tet2-mediated demethylation and hematological malignancies is unclear. The human leukemia K562 cell line is an immortalized leukemia line that serves as an in vitro model of erythroleukemia. In this study, we investigated the effect of Tet2-mediated demethylation on the apoptosis and proliferation of human leukemia K562 cells and found that knockdown of Tet2 promoted and inhibited K562 cell proliferation and apoptosis, respectively, while upregulation of TET2 enzymatic activity via alpha-ketoglutaric acid (α-KG) had the opposite effects. Therefore, the Tet2 gene acts as a potential target for the treatment of leukemia, and small molecules that target the Tet2 gene may be used to screen antitumor drugs for hematological malignancies.

Combination of chemotherapy and gaseous signaling molecular therapy: Novel β-elemene nitric oxide donor derivatives against leukemia.

This study aimed to design and synthesize active hybrids of β-elemene and nitric oxide (NO) donor pharmacophore as potential agents for treating leukemia. Derivatives reported herein exerted better inhibitory effects against human chronic myeloid leukemia K562 cells compared to β-elemene (IC50 > 100 μM). The most potent compound 18f showed an IC50 value of 0.53 μM against K562 cells, as well as a high NO release level in vitro. In the K562 xenograft tumor mice model, compound 18f effectively inhibited the growth of the tumor, with a significant inhibition rate of 73.18%. After treatment with compound 18f, the body weight of mice did not decrease, indicating that it possessed good safety profile. All these proved that compound 18f was an excellent potential agent against leukemia.

Structural Elucidation and Cytotoxic Activity of New Monoterpenoid Indoles from Gelsemium elegans.

Two new monoterpenoid indole alkaloids, gelselegandines F (1) and G (2), were isolated from the aerial parts of Gelsemium elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemical calculations. The ECD calculations were conducted at the B3LYP/6-311G(d,p) level and NMR calculations were carried out using the Gauge-Including Atomic Orbitals (GIAO) method. Structurally, the two new compounds possessed rare, cage-like, monoterpenoid indole skeletons. All isolated compounds and the total alkaloids extract were tested for cytotoxicity against four different tumor cell lines. The total alkaloids extract of G. elegans exhibited significant antitumor activity with IC50 values ranging from 32.63 to 82.24 ug/mL. In order to discover anticancer leads from the active extraction, both new indole compounds (1-2) were then screened for cytotoxicity. Interestingly, compound 2 showed moderate cytotoxicity against K562 leukemia cells with an IC50 value of 57.02 uM.

Testosterone Propionate Promotes Proliferation and Viability of Bone Marrow Mesenchymal Stem Cells while Preserving Their Characteristics and Inducing Their Anti-Cancer Efficacy

Various studies have reported the effects of testosterone on different cell types, yet bone marrow-derived mesenchymal stem cells’ cellular responses to testosterone remain unknown. To investigate the effects of testosterone propionate, an oil-soluble short-acting form of testosterone, on human bone marrow-derived mesenchymal stem cells’ proliferation and viability after 24 hours of incubation. We also investigated the impact of testosterone propionate on bone marrow-derived mesenchymal stem cell’s polarization and cytotoxicity on K562 leukemia cell line. In vitro study. We expanded commercially available bone marrow derived mesenchymal stem cells in vitro and treated them with testosterone propionate at concentrations ranging from 10-6-10-10 M for 24 hours. Ideal concentration was determined by evaluating cellular viability and proliferation with Annexin V/Propidium Iodide assay and carboxyfluorescein succinimidyl ester staining. The characteristic features of bone marrow-derived mesenchymal stem cells were evaluated by immunophenotyping and investigating their differentiation capacities. Bone marrow-derived mesenchymal stem cells’ cytotoxic properties upon testosterone propionate treatment were determined by co-culturing the cells with K562 cells and with confocal imaging investigating polarization. Testosterone propionate promoted proliferation and maintained the viability of bone marrow-derived mesenchymal stem at 10-8 M concentration. Further evaluations were conducted with the determined dose. The results showed that, apart from promoting mesenchymal stem cells’ polarization and increasing their cytotoxicity on K562 cells, testosterone propionate did not alter differentiation capacities of bone marrow-derived mesenchymal stem cells and certain cell surface markers, but led to a significant increase in HLA-DR expression. The findings reveal that testosterone propionate promotes the proliferation and survival of bone marrow-derived mesenchymal stem cells in a dose-dependent manner without hampering their differentiation capacities, induces their polarization to the pro-inflammatory phenotype, and increases their cytotoxicity on the K562 cell line.

Leukemic cells resist lysosomal inhibition through the mitochondria-dependent reduction of intracellular pH and oxidants.

Acidic lysosomes are indispensable for cancer development and linked to chemotherapy resistance. Chloroquine (CQ) and functional analogues have been considered as a potential solution to overcome the cancer progression and chemoresistance by inhibiting the lysosome-mediated autophagy and multidrug exocytosis. However, their anti-cancer efficacy in most clinical trials demonstrated modest improvement. In this study, we investigated the detailed mechanisms underlying the acquired resistance of K562 leukemic cells to CQ treatment. In response to 5-80μM CQ, the lumen pH of endosomal-lysosomal system immediately increased and gradually reached dynamic equilibrium within 24h. Leukemic cells produced more acidic organelles to tolerate 5-10μM CQ. CQ (20-80μM) concentration-dependently triggered cytosolic pH (pHi) rise, G0/G1 arrest, mitochondrial depolarization/fragmentation, and necrotic/apoptotic cell death. Oxidant induction by CQ was responsible for the mitochondria-dependent cytotoxicity and partial pHi elevation. Cells that survived the CQ cytotoxicity were accompanied with increased mitochondria. Under the 80μM CQ challenge, co-treatment with the inhibitor of F0 part of mitochondrial H+-ATP synthase, oligomycin (40nM), prevented the elevation of oxidants as well as pHi, and attenuated stresses on mitochondria, cell survival, and cell proliferation. Besides, oligomycin-treated cells obviously displayed the lysosomal peripheralization and plasma membrane blebbing, suggesting that these cells were in process of lysosomal exocytosis and microvesicle release. Enhanced motion of these secretory processes allowed the cells to exclude CQ and repair necrotic injury. Together, the oxidant production and the proton dynamic interconnection among lysosomes, mitochondria, and cytosol are crucial for leukemic susceptibility to lysosomotropic chemotherapeutics.

The effect of microvesicles derived from K562 cells on proliferation and apoptosis of human bone marrow mesenchymal stem cells.

Microvesicles (MVs) are small membrane-bound particles that act as a vehicle to transfer their contents, such as proteins, RNAs, and miRNAs, to the target cells, making them undergo several changes. Depending on the origin and the target cell, MVs may cause cell survival or apoptosis. This study investigated the effects of MVs released from the leukemic K562 cell line on the human bone marrow mesenchymal stem cells (hBM-MSCs) to evaluate changes in the survival or apoptosis of the cells in an in vitro system. In this experimental study, we added the isolated MVs from the K562 cell line to hBM-MSCs, and after three and then seven days, subsequently cell count, cell viability, transmission electron microscopy, tracing MVs by carboxyfluorescein diacetate, succinimidyl ester (CFSE) solution, flow cytometry analysis for Annexin-V/PI staining and qPCR for the evaluation of BCL-2, KI67, and BAX expression were carried out. On the 10th day of the culture, hBM-MSCs were examined by Oil red O and Alizarin Red staining to evaluate their differentiation into adipocytes and osteoblasts. There was a significant decrease in cell viability and KI67 and BCL-2 expression; however, BAX was significantly upregulated in the hBM-MSCs compared to control groups. Annexin-V/PI staining results also showed the apoptotic effects of K562-MVs on hBM-MSCs. Moreover, the differentiation of hBM-MSCs into adipocytes and osteoblasts was not observed. MVs from the leukemic cell line could affect the viability of normal hBM-MSCs and induce cell apoptosis.

Manipulation of Particle/Cell Based on Compressibility in a Divergent Microchannel by Surface Acoustic Wave.

The mechanical properties (compressibility or deformability) of cells are closely related to their death, migration, and differentiation. Accurate separation and manipulation of bioparticles based on these mechanical properties are still a challenging in the field of acoustofluidics. In this work, based on surface acoustic waves (SAW) and divergent microchannels, we developed a new method for separating and detecting particles or cells with different compressibility. The difference in acoustic radiation force (Fr) caused by compressibility are gradually amplified and accumulated by decreasing the flow velocity, and they are finally reflected in the particle migration distance. During the transverse migration process, the alternating dominance of the acoustic radiation force and the Stokes resistance force (Fs) drives the particles to create three typical migration patterns: intermittent migration, compound migration, and near-wall migration. In the present tilted SAW device, a 91% separation success rate of ∼10 μm polystyrene (PS) and polydimethylsiloxane (PDMS) particles can be achieved by optimizing the acoustic field input power and the fluid velocity. The application potential of the present divergent microchannel is validated by separating the myelogenous leukemia cell K562 and the natural killer cell NK92 that have similar densities and sizes (∼15 μm) but different compressibility. The results of this work are expected to provide valuable insights into the acoustofluidics separation and detection of the cells that are with different compressibility.

Defining cell-specific physical basis of gene expression and signatures of functional chromatin 3D interactions: integrated analysis of single-cell 3D chromatin models, RNA/ATAC-seq, and epigenetic data.

Three-dimensional structures of chromatin play important roles in gene regulation. Hi-C measurement provided a wealth of information on chromatin interactions. Emerging evidence suggests functional chromatin interactions are related to gene expression. However, gene promoters and their regulatory elements can be separated by 103-106 bp apart. Therefore, examining 3D chromatin conformations and identifying functionally long-range interactions are important for deciphering the structure-function relationship of 3D genome. Our recent work of CHROMATIX deep sampling algorithms can identify non-random chromatin interactions (5-7% of total Hi-C). These can be used to generate large ensembles of 3D single-cell chromatin conformations, accurately reproducing both single-cell capture and imaging studies, as well as population Hi-C measurements. In this study, we examine predicted ensembles of single-cell 3D chromatin conformations of loci among leukemia K562 cells, lymphoblastoid GM12878 cells, and lung fibroblast IMR90 cells. We identified small subsets of non-random chromatin interactions from Hi-C data based on large random ensembles of 3D chromatin chains folded in confined nuclear volume. These non-random interactions were used to generate ensembles of 5.0×104 single-cell 3D conformations for individual loci. We further quantified the heterogeneity of 3D chromatin conformations by clustering, with each spatial cluster and its proportion defined. In addition, we carried out an integrated analysis of RNA-seq, ATAC-seq, and epigenetic data of these cell lines. Results show that cell-specific functional chromatin interactions provide 3D basis for differential gene expression. There are well-defined signatures of 3D subpopulations of chromatin conformations involving distinctive patterns of epigenetic marks, and these signatures are strongly associated with gene differential expression.

Effects of miR-144-3p on Proliferation, Cell Cycle and Apoptosis of K562 Cells

To investigate the effects of miR-144-3p on cell proliferation, cell cycle and apoptosis of blast phase chronic myelogenous leukemia (CML) K562 cells. K562 cells were cultured in vitro and mimics negative control, hsa-miR-144-3p mimics, inhibitor negative control and miR-144-3p inhibitor were respectively transfected into K562 cells with transfection reagents. The cells were divided into five groups including blank control, mimics negative control, miR-144-3p mimics, inhibitor negative control and miR-144-3p inhibitor. After transfection, the cell proliferation activity was detected by CCK-8 assay. The cell cycle distribution and apoptosis were detected by flow cytometry. Compared with the blank control and mimics negative control groups, the proliferation rate of miR-144-3p mimics group was significantly decreased (P<0.05), the proportion of S phase cells was markedly increased (P<0.05), while the proportion of G1 phase cells was obviously decreased (P<0.05), and the apoptosis rate was significantly increased (P<0.05). Compared with the blank control and inhibitor negative control groups, the proliferation rate of miR-144-3p inhibitor group was obviously increased (P<0.05), the proportion of S phase cells was markedly decreased (P<0.05), while the proportion of G1 phase cells was obviously increased (P<0.05), and the apoptosis rate was significantly decreased (P<0.05). miR-144-3p can inhibit the proliferation and promote apoptosis of K562 cells, affect the cell cycle, and block K562 cells in S phase, which indicates that miR-144-3p is involved in the cell cycle activity of CML during blastic phase.

Bioisosteric replacement of 1H-1,2,3-triazole with 1H-tetrazole ring enhances anti-leukemic activity of (5-benzylthiazol-2-yl)benzamides

Previously, we discovered that N-(5-benzyl-1,3-thiazol-2-yl)-4-(5-methyl-1H-1,2,3-triazol-1-yl)benzamide possessed a remarkable cytotoxic effect on 28 cancer cell lines with IC50 < 50 μM, including 9 cancer cell lines, where IC50 was in the range of 2.02–4.70 μM. In the present study, we designed a novel N-(5-benzylthiazol-2-yl)amide compound 3d that was synthesized using the original bioisosteric replacement of 1H-1,2,3-triazole ring by the 1H-tetrazole ring. A significantly enhanced anticancer activity in vitro with an excellent anti-leukemic potency towards chronic myeloid leukemia cells of the K-562 line was demonstrated. Two compounds – 3d and 3l - were highly cytotoxic at nanomolar concentrations towards various tumor cells of the following lines: K-562, NCI-H460, HCT-15, KM12, SW-620, LOX IMVI, M14, UACC-62, CAKI-1, and T47D. As a highlight, the compound N-(5-(4-fluorobenzyl)thiazol-2-yl)-4-(1H-tetrazol-1-yl)benzamide 3d inhibited the growth of leukemia K-562 cells and melanoma UACC-62 cells with IС50 of 56.4 and 56.9 nM (SRB test), respectively. The viability of leukemia K-562 and pseudo-normal HaCaT, NIH-3T3, and J774.2 cells was measured by the MTT assay. Together with SAR analysis, it allowed the selection of a lead compound 3d, which demonstrated the highest selectivity (SI = 101.0) towards treated leukemic cells. The compound 3d caused DNA damage (single-strand breaks detected by the alkaline comet assay) in the leukemic K-562 cells. The morphological study of the K-562 cells treated with compound 3d revealed changes consistent with apoptosis. Thus, the bioisosteric replacement in (5-benzylthiazol-2-yl)amide scaffold proved to be a perspective approach in the design of novel heterocyclic compounds with enhanced anticancer potential.

Selenylated Imidazo[1,2-a]pyridine Induces Cell Senescence and Oxidative Stress in Chronic Myeloid Leukemia Cells.

Imidazo[1,2-a]pyridines (IPs) have been studied regarding drug development. The objective of this work was to evaluate the antileukemic capacity of IP derivatives by screening their ability as a pro-oxidant. IP derivatives were synthesized and oral bioavailability and toxicity were analyzed in silico. Redox screening was performed on human Kasumi, KG-1, K562, and Jurkat leukemia cells. The IP derivative and the most responsive leukemic cell were selected for cytotoxicity, cell proliferation, cell senescence, and oxidative stress assays. The predictive toxicity analysis showed a possible effect on the reproductive system, but without mutagenic, carcinogenic, or irritability effects. MRK-107 against K562 cells was the compound that showed the best redox profile. MRK-107 did not induce cell death in K562 and monocyte cells. However, this compound was able to decrease cell proliferation and increase cell senescence after 48 and 72 h. Furthermore, MRK-107 induced oxidative stress in K562 cells after 72 h, increasing lipid peroxidation and decreasing reduced glutathione (GSH) contents. This study demonstrated that MRK-107-induced senescence with the involvement of oxidative stress is a possible mechanism of action, addressing this compound as a potential antitumor drug against chronic myeloid leukemia.

Synthesis, Characterization and Cytotoxic Activity of Organotin(IV) Diisopropyldithiocarbamate Compounds Towards K562 Myeloid Leukaemia Cell Lines

In this work, two organotin(IV) compounds viz. triphenyltin(IV) diisopropyldithiocarbamate (1) and dimethyltin(IV) diisopropyldithio-carbamate (2) were synthesized via in situ method. Both synthesized organotin(IV) complexes were characterized by elemental, FT-IR and 1H, 12C and 119Sn NMR spectroscopies. The single-crystal structure of compound 1 was determined by X-ray single-crystal analysis. The elemental analysis data showed agreement with the suggested formulas of (C6H5)3Sn[S2CN(C3H7)2] (1) and (CH3)2Sn[S2CN(C3H7)2]2 (2). The important infrared absorbance peaks, ν(C=N) and ν(C=S), were detected in the ranges 1477-1474 cm-1 and 1038-997 cm-1 respectively. The chemical shift of carbon in the NCS2 group for compounds 1 and 2 was observed at 196.97 ppm and 198.11 ppm, respectively. The crystal structure of compound 1 showed that it is 5-coordinated and crystallized in a triclinic, P1 space group with the crystal cell parameter: a = 9.7572(1) Å, b = 11.7030(2) Å, c = 11.7602(2)Å, α = 74.419(1)°, β = 80.114(1)°, γ = 67.285(2)° and R = 0.002. The cytotoxicity (IC50) of these two compounds against K562 leukaemia cells was 0.25 μM and 4.3 μM, respectively, as assessed using MTT assay. In conclusion, the study demonstrates that both compounds showed potent cytotoxicity towards the K562 cell line tested, with compound 1 displaying a greater effect.

The enzymatic synthesis of lactose caprate using Candida rugosa lipase immobilized into ZIF-8 and investigation of its anticancer applications against K562 leukemia and HeLa cancer cells

The enzymatic synthesis of lactose caprate using <i>Candida rugosa</i> lipase immobilized into ZIF-8 and investigation of its anticancer applications against K562 leukemia and HeLa cancer cells

Synthesis of New Derivatives of Leaf-Eating Ant Toxic Gland Pheromone Compounds and Investigation of their Biological Properties

‌Background: The anti-mycobacterial characteristics of 2-pyrazinoic acid esters have been discovered through recent research. Research has demonstrated that the pyrazine ring and the alkyl part of these compounds interact with the enzyme phytynetase, which in turn inhibits the interaction between NADPH and mycobacterial fatty acids synthase, the enzyme responsible for synthesizing the fatty acids required for the cell wall of mycobacteria. Materials and Methods: Targeted pyrazinoic acid molecules have been synthesized, their structure verified by spectroscopic data, and their anti-mycobacterial activity against Mycobacterium TB H37Rv at a dose of 10 micrograms per milliliter assessed in order to test this theory. Significant anti-mycobacterial capabilities were shown by several compounds, including 3c, 3J, and 3M, which inhibited mycobacterial growth by 45.7%, 45.4%, and 51%, respectively. Findings: The results showed that the compounds exhibited little toxicity and did not inhibit macrophage cell proliferation. Pyrazinamide had significant antibacterial and antifungal activity, despite its lack of fatal action against non-tubercular mycobacteria and both Gram-positive and Gram-negative bacteria. Compound 3B, for example, exhibited excellent antibacterial properties against Gram-positive bacteria, such as S. aureus, with a minimum inhibitory concentration (MIC) of 125 micrograms per milliliter. Conversely, the compounds showed equally potent antibacterial properties against Gram-negative bacteria. Interestingly, compared to Gram-positive bacteria, the ester produced from maltol exhibited greater antibacterial efficacy against Gram-negative bacteria. Compounds synthesized with biodegradable groups also exhibited time-dependent toxicity against K562 leukemia cancer cells in MTT measurements, with compounds 3e and 3J displaying IC50 values of 25 micromolars. Conclusion: After synthesizing pyrazinoic acid monoterpene esters, spectral data was used to confirm their structures. When their biological characteristics were assessed, toxicity studies against K562 leukemia cells produced encouraging results. Through the use of Thio Ester-mediated activation of 2-pyrazinoic acid by 2, 2-dibenzothiazole disulfide and triphenylphosphine, 6-aminopenicillanic acid (6-APA) was coupled with pyrazinoic acid.

SLC25A40 Facilitates Anticancer Drug Resistance in Human Leukemia K562 Cells.

The chronic myelogenous leukemia cell line, K562/ADM is derived from the K562 cell line, which is resistant to doxorubicin (alias, adriamycin: ADM). P-glycoprotein levels are significantly higher in K562/ADM cells than in K562 cells. The overexpression of p-glycoprotein has been shown to cause drug resistance. Therefore, the present study investigated a novel mechanism underlying the drug resistance of K562/ADM cells. A gene ontology analysis demonstrated that the expression of solute carrier (SLC)-mediated transmembrane transport genes was significantly higher in K562/ADM cells than in K562 cells. The expression level of a member of the SLC family, SLC25A40 was higher in K562/ADM cells than in K562 cells. SLC25A40 is located near the ABCB1 gene. A real-time PCR analysis showed that the expression of SLC25A40, ABCB4, and ADAM22 was up-regulated. These genes are located close to SLC25A40. The down-regulation of SLC25A40 significantly decreased the mitochondrial concentration of glutathione and cell proliferation. Collectively, the present results demonstrated that the expression of SLC25A40 was up-regulated in K562/ADM cells, which enhanced to cell proliferation, and that the expression of SLC25A40 affected drug resistance to ADM.

Bioactive compounds from the fruit extract of Clausena excavata Burm. f. (Rutaceae)

• Sixteen compounds were isolated from the EtOAc extract of C. excavata fruits. • Nine compounds ( 1, 3, 5, 6, 8 – 10, 15 , and 16 ) were isolated from C. excavata for the first time. • The absolute configuration of the bioactive limonoids 15 and 16 were confirmed by the X-ray crystallography using Cu Kα radiation. • Compounds 7 (auraptene) and 14 (safrole) showed a moderate glucose uptake with ratios of 1.38-fold and 1.41-fold, respectively. • The cytotoxicity of auraptene 7, 8 , and 10 against lung cancer A549, RAW 264.7 cells, and colorectal cancer SW480 are reported for the first time in this study. Phytochemical investigation of the fruit extract of Clausena excavata Burm. f. resulted in the isolation and identification of 16 compounds, including seven coumarins ( 1 – 7 ), four phenylpropanoids ( 8 – 10 and 14 ), two benzaldehyde derivatives ( 11 and 12 ), one carbazole alkaloid ( 13 ), and two limonoids ( 15 and 16 ). Of these, nine compounds ( 1, 3, 5, 6, 8 – 10, 15 , and 16 ) were isolated from C. excavata for the first time. The absolute configuration of limonoids 15 and 16 was established by X-ray diffraction analysis using Cu Kα radiation. Some isolated compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines, namely lung cancer A549, colorectal cancer SW480, leukemic K562 cells as well as glucose uptake, glucose consumption, and antibacterial activity against Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA). Compounds 7 (auraptene) and 14 (safrole) showed moderate glucose uptake with ratios of 1.38-fold and 1.41-fold compared to the positive control (metformin, 2.25-fold). Compound 7 (auraptene) also exhibited weak cytotoxicity against lung cancer A549, colorectal cancer SW480, and leukemic K562 cells with IC 50 values of 77.2, 157.3, and 105.3 µM, respectively, while compounds 8 (( E )-piperonylprop-2-enal) and 10 (ethyl p -coumarate) exhibited weak cytotoxicity against RAW 264.7 cells and colorectal cancer SW480 cells with IC 50 values of 234.9 and 219.5 μM, respectively. Compounds 1, 3, 7 , and 14 – 16 showed a MIC of >512 µg/mL revealing them to be inactive. :

Antileukemic, Antioxidant, Anti-Inflammatory and Healing Activities Induced by a Polyphenol-Enriched Fraction Extracted from Leaves of Myrtus communis L.

Natural products have offered a number of exciting approaches in cancer treatment over the years. In this study, we investigated the prophylactic and therapeutic effects of the polyphenol-enriched fraction extracted from Myrtus communis (PEMC) on acute and chronic leukemia. According to the UHPLC-MSn, the fraction is rich in flavonoids. Protective activity of the PEMC was assessed by evaluating the antioxidant, anti-inflammatory, wound healing, and hemolysis potential in a series of in vivo and in vitro assays, while the therapeutic approach consisted of the evaluation of cytotoxic activity of the PEMC against HL60 and K562 leukemia cell lines. Safety of the fraction was also evaluated on a non-cancerous Vero cell line and by an acute toxicity test performed in mice. The PEMC demonstrated a significant anti-inflammatory and healing potential. The activities found at the dose of 100 mg/kg were better than those observed using a reference drug. The PEMC demonstrated a significant antioxidant effect and a specific cytotoxicity towards HL60 (IC50 = 19.87 µM) and K562 (IC50 = 29.64 µM) cell lines being non-toxic to the Vero cell line. No hemolytic activity was observed in vitro and no toxicity effect was found in mice. Thus, the PEMC has a pharmacological potential as both preventive and therapeutic agent. However, further research is necessary to propose its mechanism of action.

Design and synthesis of new adamantyl derivatives as promising antiproliferative agents

A series of adamantyl carboxamide derivatives containing sulfonate or sulfonamide moiety were designed as multitargeted inhibitors of ectonucleotide pyrophosphatases/phosphodiesterases (NPPs) and carbonic anhydrases (CAs). The target compounds were investigated for their antiproliferative activity against NCI-60 cancer cell lines panel. Three main series composed of 3- and 4-aminophenol, 4-aminoaniline, and 5-hydroxyindole scaffolds were designed based on a lead compound (A). Compounds 1e (benzenesulfonyl) and 1i (4-fluorobenzenesulfonyl) of 4-aminophenol backbone exhibited the most promising antiproliferative activity. Both compounds exhibited a broad-spectrum and potent inhibition against all the nine tested cancer subtypes. Both compounds showed nanomolar IC50 values over several cancer cell lines that belong to leukemia and colon cancer such as K-562, RPMI-8226, SR, COLO 205, HCT-116, HCT-15, HT29, KM12, and SW-620 cell lines. Compounds 1e and 1i induced apoptosis in K-562 leukemia cells in a dose-dependent manner. Compound 1i showed the highest cytotoxic activity with IC50 value of 200 nM against HT29 cell line. In addition, compounds 1e and 1i were tested against normal breast cells (HME1) and normal skin fibroblast cells (F180) and the results revealed that the compounds are safe toward normal cells compared to cancers cells. Enzymatic assays against NPP1-3 and carbonic anhydrases II, IX, and XII were performed to investigate the possible molecular target(s) of compounds 1e and 1i. Furthermore, a molecular docking study was performed to predict the binding modes of compounds 1e and 1i in the active site of the most sensitive enzymes subtypes.

In vitro and in silico perspectives to explain anticancer activity of a novel syringic acid analog ((4-(1H-1, 3-benzodiazol-2-yl)-2, 6-dimethoxy phenol)) through apoptosis activation and NFkB inhibition in K562 leukemia cells

Syringic acid (SA) is an active carcinogenesis inhibitor; however, the low bioavailability and unstable functional groups hinder its activity. Here, a chemically synthesized novel SA analog (SA10) is evaluated for its anticancer activity using in-vitro and in-silico studies. K562 cell line study revealed that SA10 had shown a higher rate of inhibition (IC50 = 50.40 μg/mL) than its parental compound, SA (IC50 = 96.92 μg/mL), at 50 μM concentration. The inhibition ratio was also been evaluated by checking the expression level of NFkB and Bcl-2 and showing that SA10 has two-fold increase in the inhibitory mechanism than SA. This result demonstrates that SA10 acts as an NFkB inhibitor and an apoptosis inducer. Further, molecular docking and simulation have been performed to get insights into the possible inhibitory mechanism of SA and SA10 on NFkB at the atomistic level. The molecular docking results exemplify that both SA and SA10 bind to the active site of NFkB, thereby interfering with the association between DNA and NFkB. SA10 exhibits a more robust binding affinity than SA and is firmly docked well into the interior of the NFkB, as confirmed by MM-PBSA calculations. In a nutshell, the Benzimidazole scaffold containing SA10 has shown more NFkB inhibitory activity in K562 cells than SA, which could be helpful as an ideal therapeutic NFkB inhibitor for treating cancers.