A new group of potent histone deacetylase inhibitors (HDACis) capable of inhibiting cell growth and affecting cell-cycle progression in Tohoku Hospital Pediatrics-1 (THP-1) monocytic leukaemia cells was synthesized. The inhibitors belong to a series of hydroxamic acid derivatives. We designed and synthesized a series of 22 N-hydroxycinnamamide derivatives, out of which 20 are new compounds. These compounds contain various substituted anilides as the surface recognition moiety (SRM), a p-hydroxycinnamate linker, and hydroxamic acids as the zinc-binding group (ZBG). The whole series of synthesized hydroxamic acids inhibited THP-1 cell proliferation. Compounds 7d and 7p, which belong to the category of derivatives with the most potent antiproliferative properties, exert a similar effect on cell-cycle progression as vorinostat and induce apoptosis in THP-1 cells. Furthermore, compounds 7d and 7p were demonstrated to inhibit HDAC class I and II in THP-1 cells with comparable potency to vorinostat and increase acetylation of histones H2a, H2b, H3, and H4. Molecular modelling was used to predict the probable binding mode of the studied HDACis in class I and II histone deacetylases in terms of Zn2+ ion chelation by the hydroxamate group.
- Klíčová slova
- HDACi, anticancer agents, haematological malignancies, hydroxamic acid, inhibitors of histone deacetylases,
- MeSH
- apoptóza * účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- histondeacetylasy metabolismus MeSH
- inhibitory histondeacetylas * farmakologie chemická syntéza chemie MeSH
- kyseliny hydroxamové farmakologie chemická syntéza chemie MeSH
- kyseliny kumarové farmakologie chemická syntéza chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- proliferace buněk * účinky léků MeSH
- protinádorové látky * farmakologie chemická syntéza chemie MeSH
- screeningové testy protinádorových léčiv MeSH
- simulace molekulového dockingu MeSH
- THP-1 buňky MeSH
- vorinostat farmakologie chemická syntéza chemie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- histondeacetylasy MeSH
- inhibitory histondeacetylas * MeSH
- kyseliny hydroxamové MeSH
- kyseliny kumarové MeSH
- protinádorové látky * MeSH
- vorinostat MeSH
Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma affecting children and young adults. About 30% of patients develop therapy resistance therefore new precision medicine drugs are highly warranted. Multiple rounds of structure-activity optimization of Caffeic Acid Phenethyl Ester have resulted in CM14. CM14 causes upregulation of genes involved in oxidative stress response and downregulation of DNA replication genes leading to G2/M arrest and subsequent apoptosis induction. In accordance with this, an unbiased proteomics approach, confocal microscopy and molecular modeling showed that TUBGCP2, member of the centrosomal γ-TuRC complex, is a direct interaction partner of CM14. CM14 overcomes ALK inhibitor resistance in ALCL and is also active in T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia. Interestingly, CM14 also induced cell death in docetaxel-resistant prostate cancer cells thus suggesting an unexpected role in solid cancers. Thus, we synthesized and thoroughly characterized a novel TUBGCP2 targeting drug that is active in ALCL but has also potential for other malignancies.
- MeSH
- apoptóza * účinky léků MeSH
- centrozom * účinky léků metabolismus MeSH
- fenethylalkohol * analogy a deriváty farmakologie chemie MeSH
- kyseliny kávové * farmakologie chemie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- caffeic acid phenethyl ester MeSH Prohlížeč
- fenethylalkohol * MeSH
- kyseliny kávové * MeSH
- protinádorové látky * MeSH
To explore the effects and underlying mechanisms of Mdivi-1 on three common clinical models of acute kidney injury (AKI). Three common AKI cell models were constructed, classified into the control group (human renal tubular epithelial cells [HK-2] cells), the Iohexol group (HK-2 cells treated with Iohexol), the Genta group (HK-2 cells treated with Gentamicin), and the Cis group (HK-2 cells treated with Cisplatin). To explore the optimal protective concentration of Mdivi-1 for each AKI cell model, the experimental design consisted of the following seven groups: the control group (HK-2 cells cultured in medium), three injury groups (HK-2 cells subjected to Iohexol, Gentamicin, or Cisplatin), and the corresponding protection groups (with a certain concentration of Mdivi-1 added to each injury group). Cellular survival and apoptosis, reactive oxygen species (ROS) levels, and the expression of recombinant Sirtuin 3 (SIRT3) in each group were measured. Mitochondrial fission and fusion dynamics in cells were observed under an electron microscope. To explore relevant pathways, the changes in relevant pathway proteins were analyzed through Western blotting. The half maximal inhibitory concentration (IC50) values were 150.06 mgI/ml at 6 h in the Iohexol group, 37.88 mg/ml at 24 h in the Gentamicin group, and 13.48 microM at 24 h in the Cisplatin group. Compared with the control group, the three injury groups showed increased cell apoptosis rates and higher expressions of apoptotic proteins in HK-2 cells, with an accompanying decrease in cell migration. After the addition of corresponding concentrations of Mdivi-1, the optimal concentrations were 3 µM in the Iohexo-3 group, 1 microM in the Genta-1 group, and 5 µM in the Cis-5 group, HK-2 cells showed the highest survival rate, reduced apoptosis, decreased mitochondrial ROS and SIRT3 expression, and reduced mitochondrial fission and autophagy when compared with each injury group. Further verification with Western blot analysis after the addition of Mdivi-1 revealed a reduction in the expressions of mitochondrial fission proteins DRP1, Nrf2, SIRT3, Caspase-3, Jun N-terminal Kinase (JNK)/P-JNK, NF-kappaB, Bcl2, and autophagic protein P62, as well as reduced ROS levels. Mdivi-1 had protective effects on the three common AKI cell models by potentially reducing mitochondrial fission in cells and inhibiting the production of ROS through the mediation of the NF- B/JNK/SIRT3 signaling pathway, thereby exerting protective effects. Key words AKI, Cisplatin, Gentamicin, Iohexol, Mdivi-1.
- MeSH
- akutní poškození ledvin * metabolismus patologie farmakoterapie MeSH
- apoptóza účinky léků MeSH
- buněčné linie MeSH
- lidé MeSH
- MAP kinasový signální systém účinky léků fyziologie MeSH
- mitochondriální dynamika * účinky léků fyziologie MeSH
- NF-kappa B * metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- signální transdukce * účinky léků MeSH
- sirtuin 3 * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- NF-kappa B * MeSH
- reaktivní formy kyslíku MeSH
- SIRT3 protein, human MeSH Prohlížeč
- sirtuin 3 * MeSH
Waterpipe smoking (WPS) has adverse health effects that include endothelial dysfunction with mechanisms involving oxidative stress and inflammation. Nonetheless, there is a scarcity of data on the direct impact of WPS on endothelial function. In this study, we assessed the in vitro effects of waterpipe smoke extract (WPSE) on aortic endothelial cell lines, namely the TeloHAEC. The WPSE markedly caused concentration- and time-dependent decreases in cellular viability. When compared with the control, at a concentration of 20 % and an incubation period of 48 h, the WPSE significantly increased the levels of lactate dehydrogenase, and markers of oxidative stress including thiobarbituric acid reactive substances, superoxide dismutase, catalase, and reduced glutathione. Moreover, the concentrations of proinflammatory cytokine (tumor necrosis factor alpha), and adhesion molecules (E-selectin and intercellular adhesion molecule-1) were also significantly augmented. Likewise, WPSE triggered mitochondrial dysfunction, DNA oxidative damage, as well as apoptosis in TeloHAEC cells. Similarly, cells cultured with WPSE have shown increased expression of phosphorylated nuclear factor-kappaB and hypoxia-inducible factor 1-alpha (HIF-1alpha). In conclusion, our study showed that WPSE triggers endothelial inflammation, oxidative stress, DNA damage, mitochondrial dysfunction, and apoptosis via mechanisms involving the activation of nuclear factor-kappaB and HIF-1alpha. Key words Waterpipe smoking, Aortic endothelial cells, Inflammation, Oxidative Stress.
- MeSH
- aorta * účinky léků metabolismus MeSH
- apoptóza účinky léků MeSH
- buněčné linie MeSH
- endoteliální buňky * účinky léků metabolismus MeSH
- kouř * škodlivé účinky MeSH
- kouření vodní dýmky * škodlivé účinky metabolismus MeSH
- lidé MeSH
- oxidační stres * účinky léků MeSH
- poškození DNA účinky léků MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kouř * MeSH
Early diagnosis and treatment of cancer is rapidly advancing thanks to the development of nanotechnology. Here, upconversion nanoparticles (UCNPs) are particularly promising as they are finding a wide range of applications in drug delivery and tumor imaging. In this report, a novel UCNP-based transport system is proposed for the delivery of the hypericin (Hyp) photosensitizer into malignant tumors. Core-shell NaYF4:Yb3+,Er3+@NaYF4:Nd3+ UCNPs were prepared by thermal decomposition and coated with poly(N,N-dimethylacrylamide-co-2-aminoethyl acrylate)-alendronate [P(DMA-AEA)-Ale], which endowed them with colloidal and chemical stability; finally, Hyp was conjugated. Internalization of CS-UCNP@P(DMA-AEA)-Ale-Hyp nanoparticles by Jurkat cells was successfully validated by multimodal imaging using a microstructural chamber, upconversion luminescence, and Raman microspectroscopy. After irradiation at 590 nm, CS-UCNP@P(DMA-AEA)-Ale-Hyp nanoparticles provided a markedly more effective photodynamic effect than Hyp alone at identical Hyp concentrations due to apoptosis as confirmed by caspase-3 activation. MTT assays showed that Hyp-free nanoparticles were non-cytotoxic, whereas CS-UCNP@P(DMA-AEA)-Ale-Hyp particles significantly reduced cell viability after irradiation. Considering that Hyp release from the nanoparticles was higher in the acidic environment typical of tumors compared to physiological ones, UCNP@P(DMA-AEA)-Ale-Hyp particles are a suitable candidate for future in vivo applications.
- MeSH
- anthraceny * chemie MeSH
- apoptóza účinky léků MeSH
- fluoridy chemie MeSH
- fotochemoterapie MeSH
- fotosenzibilizující látky * chemie farmakologie MeSH
- Jurkat buňky MeSH
- lidé MeSH
- multimodální zobrazování MeSH
- nanočástice * chemie MeSH
- perylen * chemie analogy a deriváty farmakologie MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- anthraceny * MeSH
- fluoridy MeSH
- fotosenzibilizující látky * MeSH
- hypericin MeSH Prohlížeč
- perylen * MeSH
AIM: This work explores the synthesis of new bi-heterocyclic hybrid compounds based on quinoline ring and investigates their potential as anticancer agents. MATERIALS & METHODS: The novel fused quinoline-thiazolo[3,2-a] benzimidazole-3(2 h)one hybrids were prepared by regioselective nucleophilic ring opening of the corresponding quinolinyl-oxiranes. In vitro cytotoxic activity was evaluated against human lung (A549) and gastric (AGS) cancer cell lines. RESULTS: Global results showed that all tested compounds have promising inhibitory properties. Compounds 17 and 18 bearing two methoxy groups on the quinoline ring have exhibited remarkable and interesting activities. The investigation of the cell death process showed that these compounds activated a caspase-dependent apoptosis pathway. Results were further supported by molecular docking studies. CONCLUSION: Both compounds exhibited good drug-like characteristics, which make them promising drug candidates.
- Klíčová slova
- Caspase-3, Quinoline, Thiazolobenzimidazole, cytotoxic activity, epoxide ring opening, hybrid compounds, molecular docking,
- MeSH
- apoptóza * účinky léků MeSH
- benzimidazoly * farmakologie chemie chemická syntéza MeSH
- chinoliny * chemie farmakologie chemická syntéza MeSH
- kaspasy * metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemie chemická syntéza MeSH
- screeningové testy protinádorových léčiv MeSH
- simulace molekulového dockingu * MeSH
- thiazoly chemie farmakologie chemická syntéza MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- benzimidazolone MeSH Prohlížeč
- benzimidazoly * MeSH
- chinoliny * MeSH
- kaspasy * MeSH
- protinádorové látky * MeSH
- quinoline MeSH Prohlížeč
- thiazoly MeSH
The copper(II), cobalt(II), and zinc(II) complexes with 2-(1H-benzimidazol-2-ylmethylsulfanylmethyl)-1H-benzimidazole (tbb) and 2-[2-[2-(1H-benzimidazol-2-yl)ethylsulfanyl]ethyl]-1H-benzimidazole (tebb), [Cu(tbb)Cl2] (1), [Co(tbb)Cl2] (2), [Zn(tbb)Cl2] (3), [Cu(tebb)Cl(H2O)]Cl (4), [Co(tebb)Cl2]n·nCH3OH (5) and [Zn(tebb)Cl(H2O)]Cl (6), have been prepared and evaluated for antiproliferative activity. The structure of (4) was proved by X-ray diffraction crystallography. The coordination compounds were tested for their cytotoxic activities in cancer cell lines in vitro. The lower IC50 values were obtained for Co(II), Cu(II), and Zn(II) complexes with tebb in comparison with tbb complexes. Complex 2 showed strong antiproliferative selectivity for leukemia CEM cells and nontoxicity towards other tested cell lines and normal human cells (BJ and RPE-1). Proapoptotic activity of 2 and 5 were weaker than positive control cisplatin, but the big advantage of these complexes was their zero-cytotoxicity for normal healthy cells in contrast to the high cytotoxicity of cisplatin. The activation of apoptotic initiation phase was detected in neuroblastoma cancer cell line SH-SY5Y where 5 was cytotoxic without fragmentation of cells. Interestingly, complexes 5, 6, and tebb, together with cisplatin, dramatically impaired the mitochondrial membrane potential of SH-SY5Y after 72 h. Taken together, we demonstrated that our compounds trigger apoptosis via the mitochondrial pathway.
- Klíčová slova
- Antiproliferative activity, Apoptosis, Benzimidazole, Biocompatibility, Coordination compound, Mitochondria,
- MeSH
- apoptóza * účinky léků MeSH
- benzimidazoly * chemie farmakologie MeSH
- kobalt chemie farmakologie MeSH
- komplexní sloučeniny * farmakologie chemie chemická syntéza MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- měď chemie farmakologie MeSH
- mitochondrie * metabolismus účinky léků MeSH
- nádorové buněčné linie MeSH
- protinádorové látky * farmakologie chemie chemická syntéza MeSH
- zinek chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- benzimidazoly * MeSH
- kobalt MeSH
- komplexní sloučeniny * MeSH
- měď MeSH
- protinádorové látky * MeSH
- zinek MeSH
An activity-guided isolation study on the EtOH extract prepared from the bulbs of Prospero autumnale yielded four new phenolic compounds, including a new stilbenoid (1), a new homoisoflavonoid derivative (8), a new homoisoflavonoid dimer (9), and an unprecedented homoisoflavone-stilbene heterodimer (10), together with six known (2-7) analogs. Their chemical structures were elucidated by spectroscopic analysis and theoretical NMR and ECD calculations. Compounds 9 and 10 are unique in their scaffolds. The in vitro cytotoxic activity of purified compounds was evaluated against eight tumor cell lines (HCT116, LoVo, DU145, PC3, HEP3B, HEPG2, MCF7, and MDA-MB-231) and one nontumor cell line (L929) by the MTS assay. Compounds 1, 2, 4, and 10 exhibited inhibition with IC50 values ranging from 8.2 to 37.6 μM. Cytotoxic cell death mechanisms were further investigated, indicating variability in apoptosis, necrosis, or cell cycle arrest.
- MeSH
- apoptóza účinky léků MeSH
- fytogenní protinádorové látky * farmakologie chemie MeSH
- isoflavony farmakologie chemie izolace a purifikace MeSH
- kořeny rostlin chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- screeningové testy protinádorových léčiv MeSH
- stilbeny * farmakologie chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fytogenní protinádorové látky * MeSH
- isoflavony MeSH
- stilbeny * MeSH
A series of eight gold(I) N-heterocyclic carbene (NHC) complexes [Au(IMes)(Ln)] based on 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene (IMes) and 7-azaindole derivatives (HLn), where n = 1-8 for HL1 = 5-fluoro-7-azaindole, HL2 = 5-bromo-7-azaindole, HL3 = 3-chloro-7-azaindole, HL4 = 3-iodo-7-azaindole, HL5 = 5-bromo-3-chloro-7-azaindole, HL6 = 5-bromo-3-iodo-7-azaindole, HL7 = 4-chloro-2-methyl-7-azaindole and HL8 = 7-azaindole, was prepared, characterised and studied for their in vitro anti-cancer and anti-inflammatory effects. The complexes showed significant cytotoxicity on human ovarian cancer cell lines (A2780, IC50 ≈ 8-19 μM and A2780R, IC50 ≈ 8-19 μM) and lowered toxicity in normal HaCat and MRC-5 cells. Cellular effects of the selected complexes 1 and 7 were evaluated in A2780 cells using flow cytometry. Moreover, the time-dependent cellular uptake in A2780 cells, a shotgun proteomic analysis, an ESI-MS study of hydrolysis and interactions with l-cysteine and reduced glutathione (GSH) were performed. Complexes 1 and 7 revealed remarkable anti-inflammatory effects via inhibition of NF-κB activity in human endothelial cells.
- Klíčová slova
- A2780, Anti-inflammatory, Cellular effects, Cytotoxicity, Gold, NHC, Proteomics,
- MeSH
- antiflogistika * farmakologie chemie MeSH
- antioxidancia * farmakologie chemie MeSH
- apoptóza * účinky léků MeSH
- endoteliální buňky účinky léků metabolismus MeSH
- heterocyklické sloučeniny * chemie farmakologie MeSH
- komplexní sloučeniny farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- methan * analogy a deriváty chemie farmakologie MeSH
- nádorové buněčné linie MeSH
- protinádorové látky * farmakologie chemie chemická syntéza MeSH
- zlato * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antiflogistika * MeSH
- antioxidancia * MeSH
- carbene MeSH Prohlížeč
- heterocyklické sloučeniny * MeSH
- komplexní sloučeniny MeSH
- methan * MeSH
- protinádorové látky * MeSH
- zlato * MeSH
Silymarin is an extract obtained from the seeds of milk thistle (Sylibum marianum L., Asteraceae) and contains several structurally related flavonolignans and a small family of flavonoids. Mouse spleen cells represent highly sensitive primary cells suitable for studying the pharmacological potential and biofunctional properties of natural substances. Cultivation of splenocytes for 24 h under standard culture conditions (humidity, 37 °C, 5% CO2, atmospheric oxygen) resulted in decreased viability of splenocytes compared to intact cells. A cytoprotective effect of silybin (SB), silychristin (SCH) and 2,3-dehydrosilybin (DHSB) was observed at concentrations as low as 5 µmol/ml. At 50 µmol/ml, these substances restored and/or stimulated viability and mitochondrial membrane potential and had anti-apoptotic effect in the order SB > DHSB > SCH. The substances demonstrated a concentration-dependent activity in restoring the redox balance based on the changes in the concentration of reactive oxygen species (ROS), hydrogen peroxide (H2O2) and nitric oxide. This was in the order DHSB > SCH > SB, which correlated with the suppressed expression of nuclear factor erythroid 2-related factor 2 (Nrf2), catalase and glutathione peroxidase. The strong stimulation of the superoxide dismutase 1 gene converting ROS to H2O2 points to its dominant role in the maintaining redox homeostasis in splenocytes, which was disrupted by oxidative stress due to non-physiological culture conditions. Our study showed significant differences in the cytoprotective, antioxidant and anti-apoptotic activities of SB, SCH, and DHSB on splenocytes exposed to mild and AAPH-induced oxidative stress.
- Klíčová slova
- 2,3-dehydrosilybin, Apoptosis, Mouse splenocytes, Redox balance, Silybin, Silychristin, Viability,
- MeSH
- antioxidancia * farmakologie MeSH
- apoptóza * účinky léků MeSH
- cytoprotekce účinky léků MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- myši inbrední BALB C * MeSH
- myši MeSH
- oxidační stres účinky léků MeSH
- peroxid vodíku MeSH
- reaktivní formy kyslíku metabolismus MeSH
- silibinin * farmakologie MeSH
- silymarin * farmakologie MeSH
- slezina * cytologie účinky léků metabolismus MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antioxidancia * MeSH
- peroxid vodíku MeSH
- reaktivní formy kyslíku MeSH
- silibinin * MeSH
- silychristin MeSH Prohlížeč
- silymarin * MeSH
