Tested Cell Lines Research Articles

Analysis of TiO2 nanoparticles accumulation in vitro

The physicochemical properties of titanium dioxide (TiO2) in nanoforms is often exploited as colorant in food, pharmaceuticals and other consumer products. However, the current evidence of potential hazards associated with titanium dioxide (TiO2) in nanoforms led to a ban of TiO2 as food additive in Europe. This regulatory decision has also an impact on thousands of pharmaceuticals. In the present study, we tested the internalisation, accumulation and resulting biological effects of different types of TiO2 nanomaterial in short and long-term vitro cultures. Even if we could demonstrate that all tested cell lines were able to take up and accumulate nanomaterial for a period of up to 30 days, the cellular responses using conventional in vitro tests were limited in all tested cell lines. Nevertheless, a transcriptomics study revealed that that the response to the accumulated material differed between two selected cell types. A keratinocyte like cell line reacted with a modified rate of keratinogenesis whereas the enterocyte like cell demonstrated mainly interactions with cell homeostasis. To further clarify possible harmful effects of TiO2, the study suggests analyzing cell/tissue type specific effects of TiO2.

N-function Heterocycles as Promising Anticancer Agents: A Case Study with a Decision Model in a Fuzzy Environment

Objective: This study aimed to evaluate the data according to five accepted criteria for the effects of twenty promising anticancer agents on five different cancer types and determine the most effective compounds for further in vitro and in vivo studies with a multi-criteria decision-making method (MCDM), which rationalizes decision making in a fuzzy environment to avoid the high cost and time requirements of further preclinical and clinical studies. Methods: Within the scope of the study, the weights of the five criteria were evaluated with the Pythagorean Fuzzy Analytic Hierarchy Process (PFAHP), which is one of the multi-criteria decisionmaking methods, and a comparison was made with the criteria weights obtained as a result of the Complex Proportional Assessment (COPRAS) method. Moreover, the effects of criteria weights calculated with PFAHP on evaluating alternatives were analyzed using different scenarios. Results: Experimentally, twenty N-heterocyclic quinoline derivatives with different substituents were identified as promising anticancer agents. In this study, the multi-criteria decision-making (MCDM) model was proposed to identify the most promising anticancer agents against all tested cell lines. Both the experimental and model results indicated that 20, 17, 19, and 7 are the most promising anticancer agents against the A549, HeLa, Hep3B, HT29, and MCF7 cell lines. Moreover, different scenarios were generated and analyzed to prove the consistency of the proposed methodology. Conclusion: MCDM strongly suggests that compounds 20, 17, 19, and 7 can be further investigated for in vivo studies.

Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines.

Pyridopyrimidines belong to a class of compounds characterized by the presence of nitrogen as heteroatoms. These compounds exhibit diverse biological effects, particularly showing promise as anticancer agents, including actions that inhibit CDK4/6. We designed and synthesized a range of substituted thiazolo-pyridopyrimidines (4a-p). Computational ADME/T analysis and molecular docking were performed using the crystal structure of CDK4/6. Subsequently, we synthesized the top-scoring compounds, characterized them using IR, NMR, and Mass spectroscopy, and assessed their impact on MCF-7 and MDAMB-231 cell lines using the SRB assay. To further evaluate stability, molecular dynamics simulations were conducted for the two most promising compounds within the binding site. The docking scores indicated stronger interactions for compounds 4a, 4c, 4d, and 4g. As a result, these specific compounds (4a, 4c, 4d, and 4g) were chosen for synthesis and subsequent screening to assess their cytotoxic effects. Remarkably, compounds 4c and 4a exhibited the most promising activity in terms of their IC50 values across both tested cell lines. Furthermore, molecular dynamics simulation studies uncovered an elevated level of stability within the 4c-6OQO complex. By integrating insights from computational, in vitro, and molecular dynamics simulation findings, compound 4c emerges as a leading candidate for future investigations. The presence of a polar hydroxyl group at the C2 position of the 8-phenyl substitution on the pyridopyrimidine rings appears to contribute to the heightened activity of the compound. Further enhancements to cytotoxic potential could be achieved through structural refinements.

Multi-functional biotinylated platinum(IV)-SAHA conjugate for tumor-targeted chemotherapy.

The development of multi-functional Pt(IV) complexes as chemotherapeutic agents has gained growing attention in medical oncology. However, the design of multi-functional tumor-targeted Pt(IV) complexes with high hydrolytic stability remains challenging. Herein, we have developed a Pt(IV) prodrug conjugated with vorinostat as a multi-functional cancer therapeutic. In this design, the octahedral Pt(IV) prodrug of a DNA damaging anticancer drug cisplatin is tethered to the cancer cell targeting biotin ligand through one of the axial sites and the other axial site of the Pt(IV) center is attached to the anticancer drug vorinostat (also known as SAHA), a histone deacetylase inhibitor (HDACi) approved by the Food and Drug Administration (FDA) for treatment of cutaneous T-cell lymphoma. The designed biotinylated Pt(iv)-SAHA (Biotin-Pt(iv)-SAHA) conjugate is hydrolytically stable but reduced to Pt(II) species under intracellularly relevant conditions and concomitantly releases cisplatin and two of its axial ligands such as SAHA and biotin. The anticancer activity of the conjugate is investigated against a panel of cisplatin-sensitive human cancer cells, including cisplatin-resistant cells. Interestingly, the conjugate exhibited significantly higher cytotoxicity than the clinically approved anticancer drug cisplatin and slightly more cytotoxicity than the HDACi SAHA in all the tested cell lines. By combining the Pt(IV) prodrug of cisplatin with SAHA in the conjugate, synergistic cytotoxicity is achieved. The imaging studies revealed that the conjugate is taken up by cancer cells and shows dose-dependent cell death. The studies on our designed multi-pronged conjugate can be further optimized to enhance its efficacy, paving the way for developing a new class of clinically relevant chemotherapeutic agents.

Second-generation piperazine derivatives as promising radiation countermeasures.

The increasing threat of nuclear incidents and the widespread use of ionizing radiation (IR) in medical treatments underscore the urgent need for effective radiation countermeasures. Despite the availability of compounds such as amifostine, their clinical utility is significantly limited by adverse side effects and logistical challenges in administration. This study focuses on the synthesis and evaluation of novel piperazine derivatives as potential radioprotective agents, with the aim of overcoming the limitations associated with current countermeasures. We designed, synthesized, and evaluated a series of 1-(2-hydroxyethyl)piperazine derivatives. The compounds were assessed for cytotoxicity across a panel of human cell lines, and for their radioprotective effects in the MOLT-4 lymphoblastic leukemia cell line and in peripheral blood mononuclear cells (PBMCs) exposed to gamma radiation. The radioprotective efficacy was further quantified using the dicentric chromosome assay (DCA) to measure DNA damage mitigation. Among the synthesized derivatives, compound 6 demonstrated the most significant radioprotective effects in vitro, with minimal cytotoxicity across the tested cell lines. Compound 3 also showed notable efficacy, particularly in reducing dicentric chromosomes, thus indicating its potential to mitigate DNA damage from IR. Both compounds exhibited superior safety profiles and effectiveness compared to amifostine, suggesting their potential as more viable radioprotective agents. This study highlights the development of novel piperazine derivatives with promising radioprotective properties. Compound 6 emerged as the leading candidate, offering an optimal balance between efficacy and safety, with compound 3 also displaying significant potential. These findings support the further development and clinical evaluation of these compounds as safer, and more effective radiation countermeasures.

Bioactivities and Medicinal Value of the Fruiting Body Extracts of Laetiporus sulphureus and Meripilus giganteus Polypore Mushrooms (Agaricomycetes).

In the present investigation methanol and acetone extracts of basidiocarps of mushrooms Laetiporus sulphureus and Meripilus giganteus were evaluated for their antimicrobial, cytotoxic and antioxidant/prooxidant effects. The antimicrobial potential was determined by the microdilution method against ten microorganisms. Cytotoxic effects were evaluated by MTT test, while changes of the redox status parameters (superoxide anion radical, nitrites and reduced glutathione) were determined spectrophotometrically on a human colorectal cancer cell line and human health fibroblasts cells. The results were measured 24 and 72 h after the treatment. Tested extracts exhibited moderate antimicrobial activity with MIC values from 0.004 to 20 mg/mL. The maximum antimicrobial activity was found in the methanol extracts of the M. giganteus against Bacillus subtilis, which was better than positive control. The acetone extract of M. giganteus with IC5072h = 13.36 μg/mL showed significant cytotoxic effect with strong cell selectivity (selectivity index = 37.42) against cancer human colorectal cancer cells. The tested extracts, especially M. giganteus acetone extract, induced an increase in oxidative stress parameters in tested cell lines, but significantly heightened it in human colorectal cancer cells. The obtained results suggest that these extracts, especially M. giganteus acetone extract, can be proposed as a novel source of nutraceuticals and pharmaceuticals.

Novel conjugates of zerumbone with quinazolin-4(3H)-ones and quinolines as potent anticancer inhibitors: Synthesis, biological evaluation and docking studies

The alkylation reaction was used to couple zerumbone with the 3-substituted quinazolinone-4(3H)-ones and quinolines, resulting in the formation of 11 new conjugates. Their structures were fully characterized by 1D-, 2D-NMR, and HRMS spectral data. The evaluation of their anti-inflammatory activity was examined by inhibiting NO production in RAW 267.4 cells. Screening for their cytotoxic activity was performed using three human cancer cell lines HepG2, SK-LU-1, and MCF-7. The results indicated that all 11 novel conjugates exhibited potent cytotoxic activity against the tested cell lines with IC50 values in the range of 1.01–9.86 µg/mL, which were stronger than those of the parent compound zerumbone. In silico EGFR inhibitory activity was also performed by docking and molecular dynamics simulation studies to find out the most potent compounds based on the main interactions of zerumbone derivatives 16a-k with important amino acids of EGFR (PDB ID 4HJO) protein in its active site.

In silico and in vitro evaluation of novel carbothioamide-based and heterocyclic derivatives of 4-(tert-butyl)-3-methoxybenzoic acid as EGFR tyrosine kinase allosteric site inhibitors

Cancer is an elaborate sequence of disease grades that include uncontrolled cell growth and division, invasion, and metastasis. Overexpression of the epidermal growth factor receptor (EGFR) causes an abnormal signal transduction and is directly linked to cancer development. Most EGFR tyrosine kinase inhibitors (TKIs) are ATP-competitive inhibitors that frequently cause EGFR mutations or chemoresistance. Therefore, targeting the EGFR TK allosteric site has become a highly sought after cancer treatment strategy. Ten new derivatives of 4-(tert-butyl)-3-methoxybenzoic acid containing carbothioamide (compounds 3a-e), triazole (compounds 4a-d) or oxadiazole (compound 5) moieties were designed as EGFR TK allosteric site inhibitors as deduced in silico. The structures of these derivatives were characterized by chemical spectroscopic methods (ATR-FTIR, 1HNMR, 13CNMR and HRESI-MS). According to the molecular docking studies, compounds 3e and 3d showed the highest docking scores (ΔG), which was confirmed by molecular dynamic (MD) simulation studies. The synthesized derivatives, specifically compounds 3d and 3e, exhibited favorable pharmacokinetic profile. In vitro, the newly synthesized derivatives were evaluated for their cytotoxicity against A549 (lung adenocarcinoma), HepG2 (hepatocellular carcinoma), and HCT-116 (colorectal) cancer cell lines via the MTT assay, flow cytometry, RT-PCR, immunoblotting, and kinase inhibition assay. The cytotoxicity results showed that compound 3d was cytotoxic to the three tested cell lines, achieving the lowest IC50 concentration against A549 cancer cells. Compound 3d targeting EGFR tyrosine kinase caused cell cycle arrest at the G2/M phase and induction of the ER-mediated apoptosis pathway. In silico and in vitro antitumor activity findings of compound 3d demonstrated that it is a promising EGFR tyrosine kinase allosteric site inhibitor.

Production of new ent-hardwickiic acid derivatives by microbial transformation and their antifungal activity

Ent-hardwickiic acid is the major compound of Copaifera pubiflora Benth oleoresin traditionally used in Brazilian folk medicine as an antimicrobial agent. Microbial transformation of ent-hardwickiic by Cunninghamella elegans ATCC 10028b resulted in two and five antifungal derivatives (four new ones) produced in the Czapek modified and Koch's K1 media, respectively. The derivatives were isolated and their structures were determined by spectral analysis, namely 1D/2D NMR and HR-ESIMS. All compounds were tested for cytotoxic and antifungal activities and they were not cytotoxic to the tested cell lines, but all derivatives showed fungicidal activity against Candida glabrata and Candida krusei, which have emerged as resistant to fluconazole. One of the yet unreported biotransformation products displayed the strongest activity with minimum fungicidal concentration values smaller than the other compounds, including fluconazole.

Synthesis and biological evaluation of novel benzenesulfonamide incorporated thiazole-triazole hybrids as antimicrobial and antioxidant agents.

A library of 20 novel benzenesulfonamide incorporating thiazole tethered 1,2,3-triazoles 1-4a-e was synthesized and screened for their antimicrobial, antioxidant,and cytotoxicity studies. Amoxicillin and fluconazole were used as reference antibacterial and antifungal drugs, respectively. Further, energies of frontier molecular orbitals were calculated for all the synthesized target compounds 1-4a-e to correlate electronic parameters with the observed biological results. Global reactivity descriptors, includinghighest occupied molecular orbitals-lowest unoccupied molecular orbitals energy gap, electronegativity, chemical hardness, chemical softness, and electrophilicity index, were also calculated for the synthesized molecules. All the tested compounds possessed moderate to excellent antibacterial potency; however, 3d and 4d exhibited the overall highest antibacterial effect (minimum inhibitory concentration [MIC] values 5-11 µM) while 2c showed the highest antifungal effect (MIC value 6 µM). Compound 3c exhibited the highest antioxidantactivity with a % radical scavenging activity value of 95.12. The cytotoxicity of the compounds 1-4a-e was also checked against an animal cell line and a plant seed germination cell line, and the compounds were found to be safe against both the tested cell lines.

Extract of microbial isolates from the western region of the Kingdom of Saudi Arabia and their applications in the field of health

Objectives: In a previous study, the presence of Aspergillus species in high-salt soil was investigated. However, it was hypothesized thatthe addition of a protein source to the soil could reveal other fungal species. This study aimed to test this hypothesis by repeating themethodology used in the previous study, but with the inclusion of a protein source. Methods: The ribosomal DNA (ITS) region was sequenced to identify the fungal isolate. The results showed that the isolate belonged toa different genus within the Aspergillus species, specifically Aspergillus sydowii. The strain was named WIS and recorded in the gene bankwith the accession number OR262340.1. The antibacterial activity of the isolated fungus was evaluated by measuring the inhibition zonediameter after exposing pathogenic bacteria to the fungus. Additionally, the anti-cancer activity of the isolate was tested on six differentcell lines, including breast cancer, hepatic cancer, and colorectal cancer. To further support the evidence of the bioactivity of this fungus,liquid chromatography-mass spectrometry (LCMS) was conducted on the fungal extract to identify its secondary medicinal metabolites.Additionally, an in-silico study was performed to predict the toxicity, pharmacokinetic properties, and safety profiles of each molecule. Results: Aspergillus sydowii exhibited antibacterial activity against both gram-positive and gram-negative bacteria. It also demonstratedexcellent anti-cancer activity on all tested cell lines. Conclusion: Future studies should focus on investigating the antimicrobial activities of this fungus against a wider range of pathogenicbacteria, particularly multidrug-resistant strains. Furthermore, it would be beneficial to study the genetic changes in bacteria and cancercells treated with these fungal extracts at the genetic level.

Heterophyllin: A New Adenia Toxic Lectin with Peculiar Biological Properties.

Ribosome-inactivating proteins (RIPs) are plant toxins that were identified for their ability to irreversibly damage ribosomes, thereby causing arrest of protein synthesis and induction of cell death. The RIPs purified from Adenia plants are the most potent ones. Here, we describe a novel toxic lectin from Adenia heterophylla caudex, which has been named heterophyllin. Heterophyllin shows the enzymatic and lectin properties of type 2 RIPs. Interestingly, in immunoreactivity experiments, heterophyllin poorly cross-reacts with sera against all other tested RIPs. The cytotoxic effects and death pathways triggered by heterophyllin were investigated in three human-derived cell lines: NB100, T24, and MCF7, and compared to ricin, the most known and studied type 2 RIP. Heterophyllin was able to completely abolish cell viability at nM concentration. A strong induction of apoptosis, but not necrosis, and the involvement of oxidative stress and necroptosis were observed in all the tested cell lines. Therefore, the enzymatic, immunological, and biological activities of heterophyllin make it an interesting molecule, worthy of further in-depth analysis to verify its possible pharmacological application.

Radiofrequency driving antitumor effect of graphene oxide-based nanocomposites: a Hill model analysis.

Aim: This report proposes using the Hill model to assess the benchmark dose, the 50% lethal dose, the cooperativity and the dissociation constant while analyzing cell viability data using nanomaterials to evaluate the antitumor potential while combined with radiofrequency therapy. Materials & methods: A nanocomposite was synthesized (graphene oxide-polyethyleneimine-gold) and the viability was evaluated using two tumor cell lines, namely LLC-WRC-256 and B16-F10. Results: Our findings demonstrated that while the nanocomposite is biocompatible against the LLC-WRC-256 and B16-F10 cancer cell lines in the absence of radiofrequency, the application of radiofrequency enhances the cell toxicity by orders of magnitude. Conclusion: This result points to prospective studies with the tested cell lines using tumor animal models.

Mapping combinatorial drug effects to DNA damage response kinase inhibitors

One fundamental principle that underlies various cancer treatments, such as traditional chemotherapy and radiotherapy, involves the induction of catastrophic DNA damage, leading to the apoptosis of cancer cells. In our study, we conduct a comprehensive dose-response combination screening focused on inhibitors that target key kinases involved in the DNA damage response (DDR): ATR, ATM, and DNA-PK. This screening involves 87 anti-cancer agents, including six DDR inhibitors, and encompasses 62 different cell lines spanning 12 types of tumors, resulting in a total of 17,912 combination treatment experiments. Within these combinations, we analyze the most effective and synergistic drug pairs across all tested cell lines, considering the variations among cancers originating from different tissues. Our analysis reveals inhibitors of five DDR-related pathways (DNA topoisomerase, PLK1 kinase, p53-inducible ribonucleotide reductase, PARP, and cell cycle checkpoint proteins) that exhibit strong combinatorial efficacy and synergy when used alongside ATM/ATR/DNA-PK inhibitors.

Isolation and structure elucidation of the compounds from Teucrium hyrcanicum L. and the investigation of cytotoxicity, antioxidant activity, and protective effect on hydrogen peroxide-induced oxidative stress

BackgroundTeucrium hyrcanicum L. (family Lamiaceae) is widely distributed in the North and Northwest of Iran. It has been used in the form of tea, tonic, and tincture for the treatment of various diseases such as cough, rheumatism, and fever.MethodsIn this study, the total phenolic and flavonoid contents, antioxidant and cytotoxic activities of methanol extract and different fractions of T. hyrcanicum were measured. Furthermore, the potential ability of T. hyrcanicum to protect against H2O2-induced oxidative stress was tested on the NIH3T3 cell line. Then, the isolation and structure elucidation of the compounds were performed on the most potent fractions. Finally, the quantification of isolated compounds in methanol extract (ME) was done by the HPLC method. Isolated phytochemicals were assessed for the cytotoxic and antioxidant activities.ResultsThe results indicated that the methanol fraction (MF) had the highest amount of phenolic and flavonoid contents (69.36 mg GAE/g extract and 68.95 mg QE/g extract). The highest radical scavenging activities were observed from MF and ME (IC50 44.32 and 61.12 μg.ml−1, respectively). The best cytotoxicity was obtained by ethyl acetate fraction (EF) against A431 and MCF7 cell lines (IC50 values of 235.4and 326.6 μg.ml−1, respectively). The pretreatment with MF exerts the highest reduction in malondialdehyde (MDA) formation (IC50 2.51 μM, p < 0.001) compared to the H2O2 group (5.77 μM). Also, MF significantly inhibited H2O2-induced Glutathione (GSH) oxidation (p < 0.001). Furthermore, two phenolic compounds, acteoside and quercetin, were isolated and identified in MF and EF, respectively. The IC50 values of acteoside and quercetin in the DPPH assay were 7.19 and 5.56 µg.ml−1, respectively. Both quercetin and acteoside significantly reduced the MDA formation and inhibited GSH oxidation, which was comparable with BHA (as a standard antioxidant) (p < 0.05). Acteoside demonstrated significant cytotoxicity against all tested cell lines (IC50 = 32 to 145 μg.ml−1). The HPLC quantification of isolated compounds revealed that the quantity of acteoside and quercetin in ME were 93.31 and 16.87 μg.mg−1, respectively.ConclusionThe isolated compounds (quercetin and acteoside) had significant antioxidant activities and revealed a protective effect on H2O2-induced oxidative stress which was comparable with BHA.

Drug Responses in Plexiform Neurofibroma Type I (PNF1) Cell Lines Using High-Throughput Data and Combined Effectiveness and Potency.

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the NF1 locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose-response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. Methods: Using concentration-response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, S = log[EFF/AC50], and (b) a relative score, ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. ΔS was applied to data from high-throughput screening (HTS) of a drug panel tested on NF1-/- tumor cells, using immortalized non-tumor NF1+/- cells as a reference. Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.

AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity.

Arsenic trioxide (ATO) targets PML/RARα and leads to miraculous success in treating acute promyelocytic leukemia. Notably, ATO also targets p53, the most frequently mutated protein in cancers, through a similar binding mechanism. However, p53-targeting ATO trials are challenging due to the poor cellular uptake and cancer selectivity of ATO. Here, we analyzed the structure-activity relationship of arsenicals and rationally developed a novel arsenical (designated AcGlcAs) by conjugating arsenic to sulfur atoms and tetraacetyl-β-d-thioglucose. AcGlcAs exhibited remarkable cellular uptake through a thiol-mediated pathway (maximally 127-fold higher than ATO), thereby potently targeting PML/RARα and mutant p53. Among the 55 tested cell lines, AcGlcAs preferentially killed cancer lines rather than normal lines. In preclinical studies, AcGlcAs significantly extended the survival of mice bearing a xenograft tumor with p53 mutation while showing high plasma stability and oral bioavailability. Thus, AcGlcAs is a potential clinical candidate for precisely treating numerous p53-mutated cancers.

Antimicrobial and Cytotoxic Secondary Metabolites from a Marine-Derived Fungus Penicillium Citrinum VM6.

Investigation of an antimicrobial and cytotoxic ethyl acetate extract prepared from solid fermentation of the marine-derived fungus Penicillium citrinum VM6 led to the isolation of eight metabolites (1-8), including one citrinin dimer dicitrinone F (1). Of these, compound 7 was isolated for the first time from the Penicillium genus and compound 1 with carbon-bridged C-7/C-7' linkage is rarely reported. All compounds (1-8) exhibited selective antimicrobial activity against the tested Gram-positive bacteria and Candida albicans with MICs of 32-256µg/mL. Compounds 1 and 8 exhibited cytotoxicity against all tested cell lines A549, MCF7, MDA-MB-231, Hela, and AGS with IC50 values of 6.7 ± 0.2 to 29.6 ± 2.2µg/mL, whereas compound 5 had selective cytotoxicity against the MCF7 cell lines with IC50 of 98.1 ± 7.8µg/mL.

Exploration of quinazoline-tethered hydroxamic acid derivatives as HDAC inhibitors for anticancer activity: Design, synthesis, molecular docking, and biological evaluation

In the past two decades, targeted cancer therapy has emerged as a novel class of anticancer therapeutics, besides traditional chemotherapy, surgery, and radiotherapy. Inhibition of HDACs represents a promising avenue for cancer therapeutics and initial success in treating select T-cell lymphomas has led to the FDA approval of four HDAC-targeted agents. The majority of currently available HDAC inhibitors have weak anticancer activity, with significant side effects. To address these drawbacks, in the present work we have designed and synthesized a novel series of histone deacetylase inhibitors combining 2-(4-substituted phenyl) quinazoline bioactive fragment as cap group and N-hydroxycinnamamide/ N-hydroxybenzamide as linker group, and evaluated for their cytotoxic activity against the three cancer cell lines (HeLa, MCF-7 and HCT-116) and HDAC inhibitory activity. All three cancer cell lines were most sensitive to the N-hydroxyacrylamide derivatives (5a-f) as compared to N-hydroxybenzamides (7a-f) derivatives. In particular, compound 5a (0.39, 0.26, 0.41 µM respectively) and 5b (0.27, 0.57, 0.32 µM respectively) were found to be the most potent derivatives among all tested cell lines. For HDAC inhibitory activity, it was found that compounds 5a, 5b, and 5d possessed comparable, even better HDAC inhibitory activity as compared to SAHA. These compounds also tested in vitro heamolytic activity, most of the compounds found biocompatible with human erythrocytes thereby evidencing the lack of haemolytic toxicity of anticancer drugs. In silico ADMET and molecular docking studies further corroborated with the experimental results. Overall, the new synthesized compounds exhibited significant HDAC and cytotoxic activity. Also, the different substituents and unsaturated bond influenced both HDAC inhibitory and cytotoxic activity. The outcome of the current work is that several potential HDAC inhibitors have emerged for further design of more potent HDAC inhibitors with better cytotoxicity.

Multiparametric cytotoxicity profiling reveals cell-line and ligand-dependent toxicity for pegylated gold nanoparticles (AuNP-PEG)

The highly tunable surface chemistry of gold nanoparticles (AuNPs) makes them ideal candidates for cancer treatments. Modification of AuNP surface chemistry creates linkage points for different surface coatings whose chemical structure regulates AuNP interactions with cells and thus plays a key role in AuNP cytotoxicity. This study looked at AuNPs functionalized with three polyethylene glycol (PEG) coatings, differing in end group functionality: PEG methyl terminated thiol (PEGCH3), PEG amine terminated thiol (PEGNH2), and PEG carboxylic acid terminated thiol (PEGCOOH). Cytotoxic effects were compared across three cell lines: human embryonic kidney (HEK293T/17), prostate cancer (PC-3), and ovarian cancer (SKOV3). Biochemical assays measured the effect AuNPs elicit on the ability of single cells to form colonies, metabolize thiazolyl blue tetrazolium bromide (MTT), or produce reactive oxygen species (ROS) using 2′,7′-dichlorofluorescein. Overall, AuNP-PEG particles were minimally toxic. HEK293T/17 colony formation was significantly decreased with all but PEGCOOH particle types, and PEGNH2 treatments significantly decreased colony formation for all three tested cell lines. ROS production was significantly increased when treated with 100 µg mL−1 AuNP PEGNH2 in all three cell lines, with PEGCH3 also showing increased ROS in PC-3 cells. PEGCH3 reduced metabolic function (MTT metabolism) in only SKOV3 cells, while PEGCOOH was toxic to HEK293T/17 cells at 100 µg mL−1. These results suggest that differing end group chemistry leads to modest cytotoxic profiles for each AuNP that are cell line and coating dependent. Elucidation of AuNP mechanisms of toxicity is a critical step in the evaluation of the future therapeutic potential for these particles.