Patients with advanced or metastatic urothelial cancer who had had a response to platinum-based chemotherapy were randomly assigned to best supportive care alone or best supportive care plus avelumab ...(an anti–PD-L1 antibody) every 2 weeks until progression. Patients receiving avelumab had significantly longer overall survival (21 months) than those receiving only best supportive care (14 months).
As ribonucleotide reductase (RNR) plays a crucial role in nucleic acid metabolism, it is an important target for anticancer therapy. The thiosemicarbazone Triapine is an efficient R2 inhibitor, which ...has entered ∼20 clinical trials. Thiosemicarbazones are supposed to exert their biological effects through effectively binding transition-metal ions. In this study, six iminodiacetate–thiosemicarbazones able to form transition-metal complexes, as well as six dicopper(II) complexes, were synthesized and fully characterized by analytical, spectroscopic techniques (IR, UV–vis; 1H and 13C NMR), electrospray ionization mass spectrometry, and X-ray diffraction. The antiproliferative effects were examined in several human cancer and one noncancerous cell lines. Several of the compounds showed high cytotoxicity and marked selectivity for cancer cells. On the basis of this, and on molecular docking calculations one lead dicopper(II) complex and one thiosemicarbazone were chosen for in vitro analysis as potential R2 inhibitors. Their interaction with R2 and effect on the Fe(III)2-Y· cofactor were characterized by microscale thermophoresis, and two spectroscopic techniques, namely, electron paramagnetic resonance and UV–vis spectroscopy. Our findings suggest that several of the synthesized proligands and copper(II) complexes are effective antiproliferative agents in several cancer cell lines, targeting RNR, which deserve further investigation as potential anticancer drugs.
Novel ruthenium(III) complexes of general formula NaRuCl
2
(L
1−3
-N,O)
2
where L
(1–3)
denote deprotonated Schiff bases (HL
1
-HL
3
) derived from 5-substituted salicyladehyde and alkylamine ...(propyl- or butylamine) were prepared and characterized based on elemental analysis, mass spectra, infrared, electron spin/paramagnetic resonance (ESR/EPR) spectroscopy, and cyclovoltammetric study. Optimization of five isomers of complex C1 was done by DFT calculation. The interaction of
C1
–
C3
complexes with DNA (Deoxyribonucleic acid) and BSA (Bovine serum albumin) was investigated by electron spectroscopy and fluorescence quenching. The cytotoxic activity of
C1
–
C3
was investigated in a panel of four human cancer cell lines (K562, A549, EA.hy926, MDA-MB-231) and one human non-tumor cell line (MRC-5). Complexes displayed an apparent cytoselective profile, with IC
50
values in the low micromolar range from 1.6 ± 0.3 to 23.0 ± 0.1 µM. Cisplatin-resistant triple-negative breast cancer cells MDA-MB-231 displayed the highest sensitivity to complexes, with Ru(III) compound containing two chlorides and two deprotonated
N
-propyl-5-chloro-salicylidenimine (hereinafter
C1
) as the most potent (IC
50
= 1.6 µM), and approximately ten times more active than cisplatin (IC
50
= 21.9 µM). MDA-MB-231 cells treated for 24 h with
C1
presented with apoptotic morphology, as seen by acridine orange/ethidium bromide staining, while 48 h of treatment induced DNA fragmentation, and necrotic changes in cells, as seen by flow cytometry analysis. Drug-accumulation study by inductively coupled plasma mass spectrometry (ICP-MS) demonstrated markedly higher intracellular accumulation of
C1
compared with cisplatin.
Graphical abstract
Objectives
The chemical composition, antimicrobial and synergistic effect, and cytotoxic activity of Citrus limon (lemon), Piper nigrum (green pepper) and Melaleuca alternifoila (tea tree) essential ...oils (EOs) were investigated.
Methods
Chemical analyses of essential oils were tested by GC‐FID and GC‐MS spectroscopy. The antimicrobial activity assay was conducted using microdilution method against several oral bacteria and Candida spp. originating from the humans with oral disorders. The synergistic antimicrobial activity was evaluated using checkerboard method. The cytotoxicity evaluation of EOs was assessed using MTT test.
Key findings
Limonene (37.5%) and β‐pinene (17.9%) were the major compounds in C. limon oil, β‐pinene (34.4%), δ‐3‐carene (19.7%), limonene (18.7%) and α‐pinene (10.4%) in P. nigrum oil and terpinen‐4‐ol (38.6%) and γ‐terpinene (21.7%) in M. alternifolia oil. The broad‐spectrum antimicrobial activity was achieved by tested three EOs, with C. limon oil being the strongest against bacteria and M. alternifolia oil strongest against fungi. The EOs demonstrated synergism; their combined application revealed an increase in antimicrobial activity. All tested essential oils showed lower cytotoxic activity in comparison with the positive control, and the obtained results confirmed a dose‐dependent activity.
Conclusions
The results of this study encourage use of tested EOs in development of a novel agent intended for prevention or therapy of corresponding oral disorders.
Two p-cymenerutheniumchlorido complexes with thiourea derivative of 7-chloroquinoline (C1) and pyridine-3-imidazole (C2) were synthesized starting from (η6-p-cymene)RuCl22 and corresponding ligands. ...The structures of complexes were determined with elemental analysis and IR, ESIMS, 1H and 13C{1H} NMR, and 2D 1H–15N correlation NMR spectroscopy. Cytotoxic activities examined by the MTT assay were performed in five human neoplastic cell lines (HeLa, K562, A549, MDA-MB-231, EA.hy926) and one nontumor human fetal lung fibroblast cell line (MRC-5). Tested complexes exhibited low micromolar activities with IC50 in the range 11.03–56.45 μM, while ligands L1 and L2 were significantly less active. Complex C1 showed cytoselective activity toward the K562 cell line (IC50 = 11.03 ± 1.39 μM) and was 3 times less active against the nontumor MRC-5 cell line. Flow cytometry analysis indicated that complexes C1 and C2 after 24 h treatment caused a concentration-dependent increase of the apoptotic sub-G1 fraction (up to 18.4%), comparable to cis-diamminedichloridoplatinum(II) (cisplatin, CDDP), although without other substantial alterations of the cell cycle. A drug-accumulation and DNA-binding study performed by ICP-MS in the K562 cell line revealed that complex C1 had a high intracellular uptake (1.38 μg Ru/106 cells), which significantly exceeded the intracellular uptake levels of CDDP (0.29 μg Pt/106 cells) and C2 (0.08 μg Ru/106 cells). However, both ruthenium complexes C1 and C2 bind to cellular DNA less efficiently in comparison to CDDP. The structure–activity relationship clearly suggested that introduction of a 7-chloroquinoline moiety in the ruthenium(II)-p-cymene complex significantly contributed to the intracellular uptake of C1 and higher cytotoxicity and cytoselectivity.
Radiation therapy is an indispensable part of various treatment modalities for breast cancer. Specifically, for non-inflammatory locally advanced breast cancer (LABC) patients, preoperative ...radiotherapy (pRT) is currently indicated as a second line therapy in the event of lack of response to neoadjuvant chemotherapy. Still approximately one third of patients fails to respond favourably to pRT. The aim of this study was to explore molecular mechanisms underlying differential response to radiotherapy (RT) to identify predictive biomarkers and potential targets for increasing radiosensitivity.
The study was based on a cohort of 134 LABC patients, treated at the Institute of Oncology and Radiology of Serbia (IORS) with pRT, without previous or concomitant systemic therapy. Baseline transcriptional profiles were established using Agilent 60 K microarray platform in a subset of 23 formalin-fixed paraffin-embedded (FFPE) LABC tumour samples of which 11 radiotherapy naïve and 3 post-radiotherapy samples passed quality control and were used for downstream analysis. Biological networks and signalling pathways underlying differential response to RT were identified using Ingenuity Pathways Analysis software. Predictive value of candidate genes in the preoperative setting was further validated by qRT-PCR in an independent subset of 60 LABC samples of which 42 had sufficient quality for data analysis, and in postoperative setting using microarray data from 344 node-negative breast cancer patients (Erasmus cohort, GSE2034 and GSE5327) treated either with surgery only (20%) or surgery with RT (80%).
We identified 192 significantly differentially expressed genes (FDR < 0.10) between pRT-responsive and non-responsive tumours, related to regulation of cellular development, growth and proliferation, cell cycle control of chromosomal replication, glucose metabolism and NAD biosynthesis II route. APOA1, MAP3K4, and MMP14 genes were differentially expressed (FDR < 0.20) between pRT responders and non-responders in preoperative setting, while MAP3K4 was further validated as RT-specific predictive biomarker of distant metastasis free survival (HR = 2.54, 95%CI:1.42-4.55, p = 0.002) in the postoperative setting.
This study pinpoints MAP3K4 as a putative biomarker of response to RT in both preoperative and postoperative settings and a potential target for radiosensitising combination therapy, warranting further pre-clinical studies and prospective clinical validation.
A series of heteropentanuclear oxalate‐bridged Ru(NO)‐Ln (4d–4f) metal complexes of the general formula (nBu4N)5Ln{RuCl3(μ‐ox)(NO)}4, where Ln=Y (2), Gd (3), Tb (4), Dy (5) and ox=oxalate anion, were ...obtained by treatment of (nBu4N)2RuCl3(ox)(NO) (1) with the respective lanthanide salt in 4:1 molar ratio. The compounds were characterized by elemental analysis, IR spectroscopy, electrospray ionization (ESI) mass spectrometry, while 1, 2, and 5 were in addition analyzed by X‐ray crystallography, 1 by Ru K‐edge XAS and 1 and 2 by 13C NMR spectroscopy. X‐ray diffraction showed that in 2 and 5 four complex anions RuCl3(ox)(NO)2− are coordinated to YIII and DyIII, respectively, with formation of Ln{RuCl3(μ‐ox)(NO)}45− (Ln=Y, Dy). While YIII is eight‐coordinate in 2, DyIII is nine‐coordinate in 5, with an additional coordination of an EtOH molecule. The negative charge is counterbalanced by five nBu4N+ ions present in the crystal structure. The stability of complexes 2 and 5 in aqueous medium was monitored by UV/Vis spectroscopy. The antiproliferative activity of ruthenium‐lanthanide complexes 2–5 were assayed in two human cancer cell lines (HeLa and A549) and in a noncancerous cell line (MRC‐5) and compared with those obtained for the previously reported Os(NO)‐Ln (5d–4f) analogues (nBu4N)5Ln{OsCl3(ox)(NO)}4 (Ln=Y (6), Gd (7), Tb (8), Dy (9)). Complexes 2–5 were found to be slightly more active than 1 in inhibiting the proliferation of HeLa and A549 cells, and significantly more cytotoxic than 5d–4f metal complexes 6–9 in terms of IC50 values. The highest antiproliferative activity with IC50 values of 20.0 and 22.4 μM was found for 4 in HeLa and A549 cell lines, respectively. These cytotoxicity results are in accord with the presented ICP‐MS data, indicating five‐ to eightfold greater accumulation of ruthenium versus osmium in human A549 cancer cells.
The metal makes the difference: A series of heteropentanuclear metal complexes of the general formula (nBu4N)5Ln{RuCl3(μ‐ox)(NO)}4, where Ln=Y (2), Gd (3), Tb (4), Dy (5) and ox=oxalate anion, were synthesized from (nBu4N)RuCl3(ox)(NO) (1) (see figure). The antiproliferative activity of ruthenium‐lanthanide complexes 2–5 in two human cancer cell lines (HeLa and A549) was found to be significantly higher than that for the previously reported Os(NO)‐Ln (5d–4f) analogues (nBu4N)5Ln{OsCl3(μ‐ox)(NO)}4 (Ln=Y (6), Gd (7), Tb (8), Dy (9)).
In vitro biological studies of four trans-platinum complexes of structural formulas trans-PtCl2(n-acetylpyridine)2 (n = 3 or 4, complex 1 or 2) and Pt(n-acetylpyridine)2Cl4 (n = 3 or 4, complex 3 or ...4) were performed in human endothelial EA.hy 926 cells, in order to evaluate and compare their cytotoxic and antiangiogenic potential. MTT results revealed that trans-Pt(II) complexes exhibited significantly lower IC50 values: 4.0±0.9 μM (1) and 2.1±0.0 μM (2), than cisplatin (27.7±1.3 μM). Combinational drug treatment with N-Acetyl-L-cysteine and L-buthioninesulfoximine strongly counteracted effect of 1 and 2, while the same treatment rather enhanced cytotoxicity of Pt(IV) analogues. ICP-MS results suggested that differential endothelial toxicity of cisplatin and trans-platinum complexes correlated to the differences in their cellular accumulation, rather than to the different affinity of DNA binding. Intracellular accumulation of complexes (ng Pt/106 cells) for 24 h treatment, decreased in order: 1>2>4>3>CDDP, while ratio of DNA binding (pg Pt/μg DNA) decreased as following: 2>1>CDDP>4>3. FACS/Annexin-V-FITC analysis, and morphological study demonstrated that the enhanced cytotoxic and apoptotic potential (18.1%) of complex 2 was related to its highest affinity to bind nuclear DNA. Pt(IV) complexes exhibited the lowest reactivity to cellular DNA and proteins. Regardless of their antiproliferative action, 1-4 at subtoxic concentrations demonstrated in vitro inhibitory effect on tubulogenesis and matrix metalloproteinases (MMPs) 2 and 9 gelatinolitic activity, while 1 and 2 additionally downregulated MMP-2 gene expression.
Two gallium(III) complexes with l-proline-thiosemicarbazone hybrids have been synthesised and comprehensively characterised. Reaction of iron(III) with the terminally dimethylated ...l-proline-thiosemicarbazone hybrid led to an oxidative cyclisation of the ligand and isolation of an iron(III) complex. The cytotoxicity of the new compounds was studied on three human cancer and one normal cell line, revealing no or low activity. The complexation reactions with iron(II), iron(III) and gallium(III) were studied in solution by using different methods. The low stability of the gallium(III) complexes at physiological pH and the low iron(II) binding affinity of the ligand precursors most probably contributes to the low antiproliferative activity of the studied substances. Display omitted
•New gallium(III) and iron(III/II) complexes with l-proline-thiosemicarbazone hybrids were synthesised.•Comprehensive characterisation(1D/2D NMR, UV–vis, ESI MS and X-ray crystallography) of gallium(III) and iron(III) complexes.•In vitro antiproliferative activity was evaluated.•Solution stability of gallium(III) and iron(III/II) complexes investigated by pH-metry, 1H NMR- and UV–vis spectroscopies.
Three new gallium(III) and iron(III) complexes with l-proline-thiosemicarbazone hybrids, namely GaCl(l-Pro-FTSC–2H)·0.7H2O·0.5CH3OH (1·0.7H2O·0.5CH3OH), GaCl(dm-l-Pro-FTSC–2H)·0.4H2O (2·0.4H2O) and FeCl(l-Pro-FTDA–H)Cl (3) were synthesised and comprehensively characterised by spectroscopic methods (1H, 13C NMR, UV–vis), ESI mass spectrometry and X-ray crystallography. The complexes are soluble in biological media to allow for assaying their antiproliferative activity. The complexes were tested in three human cancer cell lines, namely HeLa, A549 (non-small cell lung cancer), LS174 and nontumorigenic MRC5. Complex formation equilibrium processes of l-Pro-FTSC with gallium(III), iron(II) and iron(II) ions were investigated in solution. The formation of mono-ligand iron(II) and gallium(III) complexes with pentadentate ligands and relatively low aqueous solution stability was found. Between iron(III) and the ligands, a redox reaction takes place via the oxidative cyclisation of the thiosemicarbazone.
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