HL-60 Cancer Cell Lines Research Articles

Structure-activity relationships of new Organotin(IV) anticancer agents and their cytotoxicity profile on HL-60, MCF-7 and HeLa human cancer cell lines

There is a growing interest in the cancer cell growth inhibitory effects of organotin (IV) compounds and, accordingly, a new series of dimethyl-, di-(n-butyl)-, diphenyl- and chloro-phenyl tin(IV) complexes with a Schiff base core were prepared. Their binding to DNA was assessed by UV thermal denaturation showing no interaction and by UV–vis titration exhibiting moderate interaction by intercalation. Complexes having n-butyl substituents were more potent and cytotoxic against human leukemia, breast and cervical cancer cell lines than other organotin(IV) complexes tested. Unfortunately, some of these compounds showed similar cytotoxicity in a non-cancerous cell line. We may conclude that cytotoxic activity was dependent on the nature (lipophilicity and size, according to the structure-activity relationship studies) and substitution pattern on the different structures. These results may aid in the rational design of metallodrugs, expanding the scope of organotin complexes in formulating new metal based drugs with dibutyl moieties.

Esterified Derivatives of Panaxadiol and Their Inhibitory Effect on HL‐60, THP‐1, and PC‐3 Cell Lines

Panaxadiol is a dammarane-type ginsenoside having high ginseng content. The 3-hydroxy group of panaxadiol (PD) was modified by fatty acids and diacids. The modified panax glycol had enhanced anticancer activity. Twelve PD derivatives were evaluated and purified by chemical synthesis, column chromatography, co-synthesis, and identification. The human leukemia cells THP-1, HL-60, and human prostate cancer cell lines PC-3 were evaluated; PD derivatives were tested and evaluated in vitro by MTT assay. The results showed that the antitumor activities of some derivatives on three tumor cell lines were better than those of PD.

Cytotoxic 19,20-epoxycytochalasans from endophytic fungus Xylaria cf. curta

Nine new 19,20-epoxycytochalasans (1–9) were isolated from the rice fermentation extracts of endophytic fungus Xylaria cf. curta, along with four known compounds 19,20-epoxycytochalasin C (10), 18-desoxy-19,20-epoxycytochalasin C (11), 19,20-epoxycytochalasin D (12) and 5,6-dihydro-7-oxo-19,20-epoxycytochalasin C (13). Their structures and absolute configurations were determined by 1D and 2D NMR, HRESIMS, X-ray diffraction and ECD calculation. The cytotoxicity of obtained compounds (1−13) was evaluated against human cancer cell lines HL-60, A549, SMMC-7721, MCF-7, and SW480. Remarkably, compound 10 showed significant specific cytotoxicity against HL-60 cell lines with IC50 value of 1.11 μM.

Ficus carica, Ficus sycomorus and Euphorbia tirucalli latex extracts: Phytochemical screening, antioxidant and cytotoxic properties

Abstract Medicinal plants are important sources for discovering new drugs for many diseases. The aim of this study was to assess and compare the total phenolic and flavonoid contents, phytochemical compounds, antioxidant and cytotoxic activities of some medicinal plants: Ficus carica (FCE), Ficus sycomorus (FSE) and Euphorbia tirucalli (ETE) latex extracts. A significant amount of phenolics and flavonoids was recorded in the FCE, FSE and ETE of 50.2, 88.0, 10.5 mg GAE/g latex and 12.5, 34.0, 4.3 mg CE/g latex, respectively. The phenolic content of FCE, FSE and ETE were effective in scavenging free radicals of DPPH and ABTS with IC 50 values of 13.6, 7.0, 6.0 and 4.5, 6.4, 2.0 μg GAE/ml, respectively. The total antioxidant activity, using phosphomolybdenum assay, of FCE, FSE and ETE was also measured with EC 50 values of 39, 25 and 6.5 μg GAE/ml, respectively. Various phytochemical compounds with potential therapeutic values were detected in each FCE, FSE and ETE latex extract using GC-MS analysis. Most of identified phytochemical compounds are found for first time in figs or euphorbia latex extracts. Various phenolic acids and flavonoids were identified and quantified in the FCE, FSE, and ETE latex extracts with diverse therapeutic properties using HPLC analysis. The phenolic content of ETE, FCE, and FSE latex extracts exerted a potent cytotoxic effect near to doxorubicin, a common anticancer drug, against acute myeloid leukemia HL-60, breast MCF-7 and liver HepG2 cancer cell lines, respectively. Additionally, all the tested extracts didn't exert any toxicity against human normal melanocyte HFB4 cell line with concentrations up to100 μg/ml. In conclusion, the phenolic content of FCE, FSE and ETE latex extracts could be used as therapeutic agents for fighting cancer.

Physical Absorption of Folic Acid and Chitosan on Dihydroartemisinin-Loaded Poly-Lactic-Co-Glycolic Acid Nanoparticles via Electrostatic Interaction for Their Enhanced Uptake and Anticancer Effect

In this study, dihydroartemisinin (DAR), an anticancer agent with low toxicity, was loaded into poly-lactic-co-glycolic acid (PLGA) nanoparticles. The obtained PLGA cores were then coated with chitosan (CS) and/or folic acid (FA) by electrostatic interactions to enhance their anticancer and cellular uptake properties. DAR-loaded PLGA nanoparticles were prepared by the solvent evaporation method. CS and FA solutions at different ratios were dispersed concurrently into the PLGA suspension to facilitate electrostatic interactions and form nanosuspensions. The physiochemical properties of nanoparticles such as average particle size (Z), polydispersity index (PDI), zeta potential (ZP), TEM image, X-ray diffraction, and encapsulation efficiency were determined. We then determined the role of FA and CS coating on the nanoparticle surface in cytotoxicity, cellular uptake, and apoptosis. We show that the resultant nanoparticles were spherical and uniform, with a coating layer containing FA and CS covering PLGA cores with a Z of 223.5±4.28 nm, PDI of 0.209±0.03, and ZP of 15.75±1.3 mV. Both FA and CS improved the cytotoxicity of nanoparticles compared to free DAR and PLGA nanoparticles in HL-60 and KB cancer cell lines. Further, FA enhanced the cellular uptake of nanoparticles to a greater extent than CS. However, CS contributed more to apoptosis induction than FA.

Exploiting the 7-methylimidazo[1,5-a]pyrazin-8(7H)-one scaffold for the development of novel chemical inhibitors for Bromodomain and Extraterminal Domain (BET) family

The bromodomain and extraterminal (BET) family of proteins play a crucial role in promoting gene expression of critical oncogenes. Novel BET bromodomain inhibitors with excellent potency, drug metabolism and pharmacokinetics (DMPK) properties were in strong need for development. We reported a series of potential BET inhibitors through incorporation of imidazole into pyridine scaffold. Among them, a novel BET inhibitor with 7-methylimidazo[1,5-a]pyrazin-8(7H)-one core, compound 28, was considered to be the most promising for in-depth study. Compound 28 exhibited excellent BRD4-inhibitory activity with IC50 value of 33 nM and anti-proliferation potency with IC50 value of 110 nM in HL-60 (human promyelocytic leukemia) cancer cell lines. Western Blot indicated that compound 28 can effectively trigger apoptosis in BxPc3 cells by modulating the intrinsic apoptotic pathway. In conclusion, these results suggested that compound 28 has merely potential for leukemia treatment.

Bioactive rinderol and cynoglosol isolated from Cynoglossum columnae Ten. in vitro root culture

Plant in vitro cultures can effectively reduce the overexploitation of natural resources for the efficient production of natural compounds with therapeutic potential, as in case of Boraginaceae family which is well studied for its shikonin/alkannin derivatives production in biotechnological systems. In this study two naphthoquinone derivatives were isolated for the first time from in vitro root cultures of Cynoglossum columnae Ten. The structures of 2-methoxy-5O, 6-(isohex-1-ene-1,2-diyl)-5,8-dihydroxynaphthalene-1,4-dione (1) and 2-[(2S)-5-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]-5,8-dihydroxynaphthalene-1,4-dione (2) were identified by spectroscopic methods and named as rinderol and cynoglosol, respectively. Both naphthoquinones were examined for their cytotoxicity towards HL-60, HeLa and HCT-116 human cancer cell lines. Rinderol (1) showed the highest activity towards HL-60 (IC50=2.0 μg/mL), while cynoglosol (2) was selectively active against HL-60 (IC50=4.3 μg/mL). Antibacterial activity of rinderol (1) was noted for Staphylococcus epidermidis ATCC 12228 as MIC=3.91 μg/mL and Staphylococcus epidermidis MRSE 456 as MIC=7.81 μg/mL. These results present Cynoglossum columnae Ten. in vitro root culture as a new biotechnological source of natural compounds with a potential for therapeutic applications.

Synthesis, Structure, and Biological Activity of Copper and Cobalt Coordination Compounds with Substituted 2-(2-Hydroxybenzylidene)-N-(prop-2-en-1-yl)hydrazinecarbothioamides

The reaction of N-(prop-2-en-1-yl)hydrazinecarbothioamide with substituted 2-hydroxybenzaldehydes afforded the corresponding Schiff bases which were used as ligands to obtain copper and cobalt coordination compounds Cu(NL1–6)X · n H2O (X = Cl−, $$\rm{NO}_3^-$$ ; n = 0–3), Co(HL2)2NO3, and Co(NL6)2Cl. The structure of the isolated complexes was determined by NMR spectroscopy and X-ray analysis. The complexes were tested for antimicrobial and antifungal activity against S. aureus, E. coli, and yeast-like fungi. Inhibitory effect of the initial thioamides and their complexes against human myeloid leukemia HL-60 cancer cell line was also studied.

Design, synthesis and biological evaluation of 4-piperidin-4-yl-triazole derivatives as novel histone deacetylase inhibitors.

Histone deacetylase is an important member of epigenetics and a well validated target for anti-cancer drug discovery. In this study, we designed and synthesized a series of twenty-one novel hydroxamic acid-based histone deacetylase inhibitors with 4-piperidin-4-yl-triazole as the core skeleton. Most target compounds displayed excellent inhibition rates toward histone deacetylases at the concentration of 1 μM. Among them, the inhibition rates of two compounds MH1-18 and MH1-21 exceeded 90%. Furthermore, these two compounds selectively inhibited the activity of histone deacetylase 6 with low IC50 values. The high potency of them toward histone deacetylase 6 was rationalized by molecular docking studies. We found that MH1-18 and MH1-21 moderately inhibited the proliferation of four human cancer cell lines SGC-7901, NCI-H226, MCF-7, and HL-60. However, MH1-21 showed potent efficacy in suppressing the migration of MCF-7 cells. Results obtained in the current study shed light on designing potent HDAC6 inhibitors as anti-cancer agents.

Sesquiterpenes from the Leaves of Magnolia delavayi Franch. and Their Cytotoxic Activities.

Thirteen sesquiterpenes including eight new ones, magnodelavins A-H (1-8), were obtained from the 95 % ethanolic extract of the leaves of Magnolia delavayi Franch. The structures of the new compounds were determined by exhaustive 1 H-, 13 C-, 2D-NMR, UV, IR, and HR-ESI-MS data, as well as X-ray crystallographic analysis. Compounds 9 and 10 showed potent cytotoxic activities against HL-60, A-549, SMMC-7721, MCF-7, and SW480 human cancer cell lines in vitro using MTS assay.

Effective enmein-type mimics of clinical candidate HAO472: Design, synthesis and biological evaluation

A series of enmein-type diterpenoid amino acid ester derivatives (14–22) were designed and synthesized according to l-alanine-(14-oridonin) ester trifluoroacetate (clinical candidate HAO472). Their antiproliferative activities were tested against SGC-7901, Bel-7402, HL-60, PC-3, A549 and K562 cancer cell lines and L-02 normal liver cells. The results showed that compound 19 possessed the most potent cytotoxicity with IC50 s at sub-micromolar level against human hepatoma Bel-7402 and chronic myelogenous leukemia K562 cells and more potent than l-alanine-(14-oridonin) ester (23). More importantly, 19 displayed 70-fold less cytotoxicity than parent 3 (IC50 = 25.47 μM) against L-02 cells, which exhibited certain selectivity. Further mechanism study in Bel-7402 cells revealed that 19 could induce apoptosis, G1 phase cell cycle arrest and mitochondrial dysfunction. Western blot results of caspase-3, Bax and cytochrome c upregulation and pro-caspase-3, Bcl-2 and Bcl-xL downregulation confirmed the intrinsic pathways. Overall, these data collectively demonstrated the high efficiency and selectivity of 19, l-phenylalanine-enmein-type diterpenoid ester, which inspires further and effective application as a potential antitumor candidate.

Synthesis of Bioactive Side-Chain Analogues of TAN-2483B.

The fungal metabolite TAN-2483B has a 2,6-trans-relationship across the pyran ring of its furo[3,4-b]pyran-5-one core, which has thwarted previous attempts at its synthesis. We have now developed a chiral pool approach to this core and prepared side-chain analogues of TAN-2483B. The synthesis relies on ring expansion of a reactive furan ring-fused dibromocyclopropane and alkynylation of the resulting pyran. The furan ring is constructed by palladium-catalysed carbonylative lactonisation. Various side-chains are appended through Wittig-type chemistry. The prepared analogues showed micromolar activity towards cancer cell lines HL-60, 1A9 and MCF-7 and certain human disease-relevant kinases, including Bruton's tyrosine kinase (Btk).

3-Hydroxyisoindolin-1-one derivates: Synthesis by palladium-catalyzed C[sbnd]H activation as BRD4 inhibitors against human acute myeloid leukemia (AML) cells

Bromodomain protein 4 (BRD4) is a member of the bromodomain and extra-terminal domain (BET) protein family, which plays a key role in transcriptional regulation. Recent biological and pharmacological studies have enabled linking of the BET bromodomains with diseases, including inflammation and cancer, suggesting that bromodomains are druggable targets. In this study, we made further structural modifications of our previously reported BRD4 inhibitors, to develop new chemical scaffold 3-Hydroxyisoindolin-1-One. Then a series of compounds (10a-q) were synthesized via palladium-catalyzed CH activation and BRD4-inhibitory activities and anti-proliferative effects of these compounds were evaluated. Compound 10e exhibited excellent BRD4-inhibitory activity with IC50 value of 80 nM and anti-proliferation potency with IC50 value of 365 nM in HL-60 (humanpromyelocytic leukemia) cancer cell lines. We have demonstrated compound 10e modulated the intrinsic apoptotic pathway. In conclusion, these results suggested that compound 10e could be utilized as a BRD4 inhibitor for further leukemia treatment.

Unusual constituents from the medicinal mushroom Ganoderma lingzhi.

Extensive studies have revealed that triterpenoids, meroterpenoids, and polysaccharides are the main constituents of the well-known traditional Chinese medicinal mushroom Ganoderma. In this study, we report seven previously undescribed sesquiterpenoids, including six gymnomitranes (1–6) and a novel type of sesquiterpenoid (8), together with a polyketide (7) and a known steroid (9) from the fruiting bodies of Ganoderma lingzhi, a fungus used as traditional medicine and food supplement in East Asia for ages. The structures of 1–8 were deduced by analysis of spectroscopic data, X-ray single crystal diffractions and TDDFT/ECD calculations. Compound 8 possessed an unusual 14(7→6)-cuparane scaffold. Compound 9 exhibited weak cytotoxicity against the five human cancer cell lines HL-60, MCF-7, SW480, A549, and SMMC-7721 with IC50 values of 18.0–32.3 μM. A simple structure-activity-relationship (SAR) investigation by acetylating the 5-OH of 9 (9a) suggested that the 5-OH is essential for its cytotoxicity. Additionally, the biosynthetic pathways for compounds 2 and 8 are discussed.

Cyclodepsipeptides and Sesquiterpenes from Marine-Derived Fungus Trichothecium roseum and Their Biological Functions.

On the basis of the ‘one strain, many compounds’ (OSMAC) strategy, chemical investigation of the marine-derived fungus Trichothecium roseum resulted in the isolation of trichomide cyclodepsipeptides (compounds 1–4) from PDB medium, and destruxin cyclodepsipeptides (compounds 5–7) and cyclonerodiol sesquiterpenes (compounds 8–10) from rice medium. The structures and absolute configurations of novel (compounds 1, 8, and 9) and known compounds were elucidated by extensive spectroscopic analyses, X-ray crystallographic analysis, and ECD calculations. All isolated compounds were evaluated for cytotoxic, nematicidal, and antifungal activities, as well as brine shrimp lethality. The novel compound 1 exhibited significant cytotoxic activities against the human cancer cell lines MCF-7, SW480, and HL-60, with IC50 values of 0.079, 0.107, and 0.149 μM, respectively. In addition, it also showed significant brine shrimp lethality, with an LD50 value of 0.48 μM, and moderate nematicidal activity against Heterodera avenae, with an LC50 value of 94.9 μg/mL. This study constitutes the first report on the cytotoxic and nematicidal potential of trichomide cyclodepsipeptides.

Fluorescence intensity modulation of CdSe/ZnS quantum dots assesses reactive oxygen species during chemotherapy and radiotherapy for cancer cells.

Quantum dots (QDs) are semiconductor nanoparticles ranging in size from 2 to 10 nm. QDs are increasingly being developed for biomedical imaging, targeted drug delivery and green energy technology. These have led to much research on QD interactions with various physical, chemical and biological systems. For biological systems, research has focused on the biocompatibility/cytotoxicity of QDs in the context of imaging/therapy. However, there is a paucity of work on how biological systems and bioactive molecules might be used to alter the optoelectronic properties of QDs. Here, it is shown that these properties can be altered by reactive oxygen species (ROS) from chemotherapeutic media and biological cells following controlled changes in cellular activities. Using CdSe/ZnS core-shell QDs, spectroscopic analysis of optically excited QDs with HL60, K562 and T98G cancer cell lines is performed. Our results show statistically significant (P < 0.0001) modulation of the fluorescence emission spectra of the QDs due to the ROS produced by common chemotherapeutic drugs, daunorubicin and doxorubicin and by cells following chemotherapy/radiotherapy. This optical modulation, in addition to assessing ROS generation, will possibly enhance applications of QDs in simultaneous diagnostic imaging and nanoparticle-mediated drug delivery as well as simultaneous ROS assessment and radiosensitization for improved outcomes in cancer treatments. Reactive molecular species produced by biological cells and chemotherapeutic drugs can create electric fields that alter the photophysical properties of QDs, and this can be used for concurrent monitoring of cellular activities, while inducing changes in those cellular activities.

Effects of Global O-GlcNAcylation on Galectin Gene-expression Profiles in Human Cancer Cell Lines.

The effects of O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA) inhibitors on galectin gene expression profiles were examined in MCF7, HT-29, and HL-60 cancer cell lines. Cell cultures were treated for 24 h with OGA inhibitor thiamet G or OGT inhibitor 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-5-thio-α-D-glucopyranose, and global O-GlcNAc levels and expression of galectin genes were determined using an immunodot blot assay and real-time quantitative polymerase chain reaction. Two galectin genes, LGALS3 in MCF7 cells and LGALS12 in HL-60 cells, were up-regulated by O-GlcNAc, whereas other cell-specific galectins were unresponsive to changes in O-GlcNAc level. Of interest, basal levels of O-GlcNAc in resting HL-60 and HT-29 cells were significantly higher than those in cells differentiated into neutrophilic or enterocytic lineages, respectively. O-GlcNAc-mediated signaling pathways may be involved in regulating the expression of only a limited number of galectin genes. Additional O-GlcNAc-dependent mechanisms may work at the protein level (galectin secretion and intracellular localization) and warrant further investigation.

A Pair of Enantiomeric Bis- seco-abietane Diterpenoids from Cryptomeria fortunei.

(±)-Cryptomeriolide, a pair of racemic bis- seco-abietane diterpenoids, were isolated from the bark of Cryptomeria fortunei. The separation of enantiomers was achieved by using chiral stationary phase HPLC. Their structures including the absolute configuration and conformations in solution and solid state were determined by extensive analysis of spectroscopic data, single-crystal X-ray diffraction, and comparison of calculated and experimental electronic circular dichroism data. A bioinspired one-pot enantiomeric synthesis of 1a and 1b was accomplished via a readily made intermediate orthoquinone from sugiol. All compounds including the synthetic intermediates were assayed for their cytotoxic activities on human cancer cell lines HL-60, A549, and SGC7901.

Cytotoxic polyketides from endophytic fungus Phoma bellidis harbored in Ttricyrtis maculate

Four new polyketides, namely bellidisins A-D (1-4), were isolated from rice fermentation extract of endophytic fungus Phoma bellidis, along with three known compounds pinolidoxin (5), 5,6-epoxypinolidoxin (6), and 2-epi-herbarumin II (7). Their structures and absolute configurations were determined by 1D and 2D NMR, HRESIMS and ECD calculation. Their cytotoxicity was evaluated against human cancer cell lines HL-60, A549, SMMC-7721, MCF-7, and SW480. Compound 4 showed significant cytotoxicity on these five cell lines with IC50 value ranged from 3.40 to 15.25 μM, which is stronger than cisplatin (4.86–27.70 μM).

Understanding the cytotoxic effects of new isovanillin derivatives through phospholipid Langmuir monolayers

Twenty-one isovanillin derivatives were prepared in order to evaluate their cytotoxic properties against the cancer cell lines B16F10-Nex2, HL-60, MCF-7, A2058 and HeLa. Among them, seven derivatives exhibited cytotoxic activity. We observed that for obtaining smaller IC50 values and for increasing the index of selectivity, two structural features are very important when compared with isovanillin (1); a hydroxymethyl group at C-1 and the replacement of the hydroxyl group at C-3 by different alkyl groups. As the lipophilicity of the compounds was changed, we decided to investigate the interaction of the cytotoxic isovallinin derivatives on cell membrane models through Langmuir monolayers by employing the lipids DPPC (1,2-diplamitoyl-sn-glycero-3-phosphocoline) and DPPS (1,2-diplamitoyl-sn-glycero-3-phosphoserine). The structural changes on the scaffold of the compounds modulated the interaction with the phospholipids at the air-water interface. These results were very important to understand the biophysical aspects related to the interaction of the cytotoxic compounds with the cancer cell membranes.