Anticancer Drug Imatinib Research Articles

Insights Into the Mechanism of Anticancer Drug Imatinib Revealed Through Multi-Omic Analyses in Yeast.

Imatinib mesylate is a receptor tyrosine kinase inhibitor drug with broad applications in cancer therapeutics, for example, in chronic myeloid leukemia and gastrointestinal stromal tumors. In this study, new multi-omics findings in yeast on the mechanism of imatinib are reported, using the model organism Saccharomyces cerevisiae. Whole-genome analysis of the transcriptional response of yeast cells following long-term exposure to imatinib, flux-balance analysis (FBA), and modular analysis of protein/protein interaction network consisting of proteins encoded by differentially expressed genes (DEGs) were performed. DEGs indicated that carbon, nitrogen, starch, sucrose, glyoxylate/dicarboxylate metabolism, valine and leucine degradation, and tricarboxylic acid cycle (TCA) were significantly upregulated. By contrast, ribosome biogenesis, pentose/glucuronate interconversion, tryptophan/pyruvate metabolic pathways, and meiosis were significantly downregulated. FBA revealed that a large set of metabolic pathways was altered by imatinib to compensate cancer-associated metabolic changes. Integration of transcriptome and interactome (protein/protein interactions) data helped to identify the core regulatory genes and pathways through elucidation of the active subnetworks. It appears that imatinib may also contribute to antitumoral immune response in the tumor microenvironment and most of the metabolic rearrangements are at posttranscriptional level. Furthermore, additional support for possible contribution of thiamine/pyridoxal phosphate biosynthesis and mitogen-activated protein kinase pathway to drug resistance is noted. This report advances multi-omics understanding of the mechanism of imatinib, and by extension, offers new molecular avenues toward precision medicine and discovery of novel drug targets in cancer therapeutics.

Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib.

BackgroundPlatelets play important roles in cancer progression and metastasis, as well as in cancer-associated thrombosis (CAT). Tyrosine kinases are implicated in several intracellular signaling pathways involved in tumor biology, thus tyrosine kinase inhibitors (TKIs) represent an important class of anticancer drugs, based on the concept of targeted therapy.PurposeThe objective of this study is the design and synthesis of analogues of the TKIs imatinib and nilotinib in order to develop tyrosine kinase inhibitors, by investigating their molecular requirements, which would express antiplatelet properties.MethodsBased on a recently described by us improved approach in the preparation of imatinib and/or nilotinib analogues, we designed and synthesized in five-step reaction sequences, 8 analogues of imatinib (I–IV), nilotinib (V, VI) and imatinib/nilotinib (VII, VIII). Their inhibitory effects on platelet aggregation and P-selectin membrane expression induced by arachidonic acid (AA), adenosine diphosphate (ADP) and thrombin receptor activating peptide-6 (TRAP-6), in vitro, were studied. Molecular docking studies and calculations were also performed.ResultsThe novel analogues V–VIII were well established with the aid of spectroscopic methods. Imatinib and nilotinib inhibited AA-induced platelet aggregation, exhibiting IC50 values of 13.30 μΜ and 3.91 μΜ, respectively. Analogues I and II exhibited an improved inhibitory activity compared with imatinib. Among the nilotinib analogues, V exhibited a 9-fold higher activity than nilotinib. All compounds were less efficient in inhibiting platelet aggregation towards ADP and TRAP-6. Similar results were obtained for the membrane expression of P-selectin. Molecular docking studies showed that the improved antiplatelet activity of nilotinib analogue V is primarily attributed to the number and the strength of hydrogen bonds.ConclusionOur results show that there is considerable potential to develop synthetic analogues of imatinib and nilotinib, as TKIs with antiplatelet properties and therefore being suitable to target cancer progression and metastasis, as well as CAT by inhibiting platelet activation.

An expeditious entry to rare tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-ones: A single-step gateway synthesis of glochidine congeners

A single-step gateway synthesis of glochidine and its congeners that possess the rare uncommon tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidine core was developed employing histamine and readily available γ-ketoesters. Key features of the developed reaction involve tandem three C–N bonds formation and concomitant annulation of two rings in one pot to access this unique and complex tricyclic structure. Exploration of the unknown bioactivity of these compounds revealed that they elicit antiproliferative activity comparable to the anticancer drug imatinib against 6 cancer cell lines.

Electrocatalytic generation of homogeneous and heterogeneous hydroxyl radicals for cold mineralization of anti-cancer drug Imatinib

The effective removal of anti-cancer drug Imatinib (IMA) from water was explored by electrochemical advanced oxidation processes electro-Fenton (EF) and anodic oxidation (AO-H2O2) using different kinds of anode material: Pt, DSA (Ti/RuO2-IrO2), BDD and sub-stoichiometric titanium oxide (Ti4O7) and carbon felt cathode. IMA was then destroyed by hydroxyl radicals (OH) generated in the system. A series of comparison experiments including oxidative degradation kinetics of IMA, total organic carbon (TOC) removal and mineralization efficiency were conducted at ambient temperature. In both cases, DSA and Pt anodes were less effective for the anodic oxidation and mineralization of IMA compared to Ti4O7 and BDD anodes. Complete mineralization of 0.07 mM (34.5 mg L−1) IMA solution (corresponding to 24.11 mg L−1 initial TOC) was obtained both in EF and AO-H2O2 processes with BDD anode at 300 mA. The Ti4O7 anode was proved not advantageous to decay kinetics of IMA under high current densities (12.5 and 20.8 mA cm−2), while exhibited better mineralization performance than DSA and Pt anode, reaching 82% TOC removal efficiency in EF and 73% in AO-H2O2 processes at 8 h electrolysis with 12.5 mA cm−2. Besides, the formation and evolution of intermediate products including short-chain carboxylic acids and N-based inorganic ions (NH4+, NO3−) during mineralization of IMA solution were monitored by GC–MS, ion exclusion HPLC and ion chromatography, respectively. Finally, a plausible degradation pathway for degradation of IMA by OH was proposed according to the intermediates detected by HPLC and GC–MS.

Cytotoxic Effects of Some Flavonoids and Imatinib on the K562 Chronic Myeloid Leukemia Cell Line: Data Analysis Using the Combination Index Method

Background:Flavonoids are natural compounds with antioxidant, anticarcinogenic, and anti-inflammatory effects.Aims:To determine the cytotoxic effects of flavonoids and drug resistance related to P-gp on K562 human chronic myeloid leukemia cells. We also aimed to evaluate the therapeutic potential of imatinib and flavonoid combinations.Study Design:Cell culture study.Methods:In this study, K562 cells were treated with apigenin, luteolin, 5-desmethyl sinensetin and the anticancer drug imatinib mesylate. The effect of flavonoids on K562 cell proliferation was detected using the 3-(4,5-dimethylthiazolyl)2,5‑diphenyl‑tetrazolium bromide assay. Concentrations of apigenin, luteolin, and 5-desmethyl sinensetin ranging from 25 to 200 μM and of imatinib from 5 to 50 μM administered for 72 h were studied. Apoptosis/necrosis and P-gp activity were measured using flow cytometry. The combined effects of different concentrations of flavonoids with imatinib were evaluated according to combination index values calculated using CompuSyn software.Results:In our study, the IC50 values for apigenin, luteolin, and 5-desmethyl sinensetin were found to be 140 μM, 100 μM, and >200 μM, respectively. Luteolin (100 μM) had the highest cytotoxic activity of these flavonoids. These results were statistically significant (p<0.05). Among the flavonoids studied, the combination of luteolin and imatinib was the most effective and is therefore recommended for its cytotoxic activity in the K562 cell line. After 72 h of incubation at their respective IC50 concentrations, all flavonoids were associated with an apoptosis rate of approximately 50%. P-glycoprotein activity was increased in all groups. Combination treatment may provide better outcomes in terms of cytotoxicity and thus reduce the dosages of imatinib used.Conclusion:The combination of some flavonoids and imatinib mesylate may increase the cytotoxic effect; However, the antagonistic effect should be considered in combined use on k562 cells.

Cytotoxic Effects of Some Flavonoids and Imatinib on K562 Chronic Myeloid Leukemia Cell Line: Data Analysis Using the Combination Index Method

Background: Flavonoids are natural compounds with antioxidant, anticarcinogenic, and anti-inflammatory effects.Aims: To determine the cytotoxic effects of flavonoids and drug resistance related to P-gp on K562 human chronic myeloid leukemia cells. We also aimed to evaluate the therapeutic potential of imatinib and flavonoid combinations.Study Design: Cell culture study.Methods: In this study, K562 cells were treated with apigenin, luteolin, 5-desmethyl sinensetin and the anticancer drug imatinib mesylate. The effect of flavonoids on K562 cell proliferation was detected using the 3-(4,5-dimethylthiazolyl)2,5‑diphenyl‑tetrazolium bromide assay. Concentrations of apigenin, luteolin, and 5-desmethyl sinensetin ranging from 25 to 200 &mu;M and of imatinib from 5 to 50 &mu;M administered for 72 h were studied. Apoptosis/necrosis and P-gp activity were measured using flow cytometry. The combined effects of different concentrations of flavonoids with imatinib were evaluated according to combination index values calculated using CompuSyn software.Results: In our study, the IC50 values for apigenin, luteolin, and 5-desmethyl sinensetin were found to be 140 &mu;M, 100 &mu;M, and &gt;200 &mu;M, respectively. Luteolin (100 &mu;M) had the highest cytotoxic activity of these flavonoids. These results were statistically significant (p&lt;0.05). Among the flavonoids studied, the combination of luteolin and imatinib was the most effective and is therefore recommended for its cytotoxic activity in the K562 cell line. After 72 h of incubation at their respective IC50 concentrations, all flavonoids were associated with an apoptosis rate of approximately 50%. P-glycoprotein activity was increased in all groups. Combination treatment may provide better outcomes in terms of cytotoxicity and thus reduce the dosages of imatinib used. Conclusion: The combination of some flavonoids and imatinib mesylate may increase the cytotoxic effect; However, the antagonistic effect should be considered in combined use on k562 cells.

Label-Free Quantification of Anticancer Drug Imatinib in Human Plasma with Surface Enhanced Raman Spectroscopy.

Therapeutic drug monitoring (TDM) for anticancer drug imatinib has been suggested as the best way to improve the treatment response and minimize the risk of adverse reactions in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST) patients. TDM of oncology treatments with standard analytical methods, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) is, however, complex and demanding. This paper proposes a new method for quantitation of imatinib in human plasma, based on surface enhanced raman spectroscopy (SERS) and multivariate calibration using partial least-squares regression (PLSR). The best PLSR model was obtained with three latent variables in the range from 123 to 5000 ng/mL of imatinib, providing a standard error of prediction (SEP) of 510 ng/mL. The method was validated in accordance with international guidelines, through the estimate of figures of merit, such as precision, accuracy, systematic error, analytical sensitivity, limits of detection, and quantitation. Moreover, the feasibility and clinical utility of this approach have also been verified using real plasma samples taken from deidentified patients. The results were in good agreement with a clinically validated LC-MS/MS method. The new SERS method presented in this preliminary work showed simplicity, short analysis time, good sensitivity, and could be considered a promising platform for TDM of imatinib treatment in a point-of-care setting.

A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics.

Drug-target binding kinetics has recently emerged as a sometimes critical determinant of in vivo efficacy and toxicity. Its rational optimization to improve potency or reduce side effects of drugs is, however, extremely difficult. Molecular simulations can play a crucial role in identifying features and properties of small ligands and their protein targets affecting the binding kinetics, but significant challenges include the long time scales involved in (un)binding events and the limited accuracy of empirical atomistic force fields (lacking, e.g., changes in electronic polarization). In an effort to overcome these hurdles, we propose a method that combines state-of-the-art enhanced sampling simulations and quantum mechanics/molecular mechanics (QM/MM) calculations at the BLYP/VDZ level to compute association free energy profiles and characterize the binding kinetics in terms of structure and dynamics of the transition state ensemble. We test our combined approach on the binding of the anticancer drug Imatinib to Src kinase, a well-characterized target for cancer therapy with a complex binding mechanism involving significant conformational changes. The results indicate significant changes in polarization along the binding pathways, which affect the predicted binding kinetics. This is likely to be of widespread importance in binding of ligands to protein targets.

In Vitro Anticancer Drug Delivery Using Amphiphilic Poly(N‐vinylpyrrolidone)‐b‐Polyketal‐b‐Poly(N‐vinylpyrrolidone) Block Copolymer as Micellar Nanocarrier

AbstractWe have first synthesized acid‐degradable alkyne‐terminated aliphatic polyketal and thereof synthesized novel pH‐responsive double hydrophilic amphiphilic block copolymer of poly(N‐vinyl pyrrolidone) (PNVP) and aliphatic polyketal (PK) (PNVP‐b‐PK‐b‐PNVP via click chemistry upon reaction with azide‐terminated PNVP. Formation of block copolymer is confirmed by proton nuclear magnetic resonance, gel permeation chromatography, thermogravimetry, differential scanning calorimetry, and fluorescence spectroscopy techniques. pH‐dependent degradation study of the block copolymer shows faster degradation at lower pH. Transmission electron microscopy (TEM) has revealed the formation of tiny (∼3.8 nm) micellar nanoparticles. Loading of the anticancer drugs doxorubicin (Dox) and imatinib in the micelle is confirmed from UV‐Visible, and TEM studies. Drug release study from drug‐loaded micelles has shown that imatinib is being released faster than Dox and both systems have shown higher load release at acidic pH of 6.4. Doxorubicin‐ and imatinib‐ loaded micelles demonstrate significant tumoricidal properties against parental and drug resistant human erythroleukemia K‐562 and Dalton's lymphoma cells with respect to enhanced cellular uptake, cytotoxicity and growth inhibition.

Abstract 3100: Replacing fetal calf serum by human platelet lysate in cancer research and toxicology

Abstract Experiments with cultured mammalian cells represent a common in vitro alternative to animal experiments. Fetal calf serum (FCS) is the most commonly used medium supplement. FCS contains a mixture of largely undefined growth factors and cytokines. Since FCS is received from unborn calves older than three months, it represents a massive burden for the pregnant cows and their fetuses. A needle is inserted into the heart of the fetus to collect blood. Since the animal is not under anesthesia, it may suffer pain and discomfort. Furthermore, the undefined nature of FCS is a source of experimental variation, undesired immune responses, and possible contaminations. Thus, alternative, defined, valid, and reliable medium supplements should be identified. We follow the principles of the 3Rs (Replacement, Reduction, Refinement). We established a method to receive human platelet lysate (hPL) from human blood platelets. We investigated if hPL represents potential true alternative for FCS in cell culture experiments and thereby the cruel slaughtering of unborn fetuses. hPL is received by freeze and thawing cycles and centrifugation steps. We successfully adapted three human leukemia cell lines (K562, NB4 and MV4-11) and HCT116 colon cancer cells to culture medium containing 1-5% hPL. We analyzed cell morphology by microscopy. Cell growth kinetics were examined by counting and cell cycle distributions were investigated by flow cytometry. Protein expression patterns were determined globally by global scale proteomics. We additionally determined possible FCS- or hPL-dependent reactions of cells to the well-established anti-cancer drugs Irinotecan, Hydroxyurea and Imatinib, and to epigenetic modulators of the HDAC inhibitor family (FK228 and the new, highly selective HDAC6 inhibitor Marbostat-100) by flow cytometry and Western blot. In these tests, we particularly focused on the expression of the pan-leukemic marker and transcription factor Wilms tumor 1 (WT1) and on the tumor suppressor p53. All tested cell lines grow with 5% FCS and 5% hPL. Cell morphology, cell cycle distribution, and protein expression patterns were not affected by such different culture conditions in resting and treated cells. We further show that the class I HDACs HDAC1-3, but not HDAC6, regulate WT1 and p53. Our findings demonstrate that hPL is a promising replacement for animal serum. Citation Format: Oliver H. Krämer. Replacing fetal calf serum by human platelet lysate in cancer research and toxicology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3100.

ATP-based cell viability assay is superior to trypan blue exclusion and XTT assay in measuring cytotoxicity of anticancer drugs Taxol and Imatinib, and proteasome inhibitor MG-132 on human hepatoma cell line HepG2.

Drug-induced liver injury (DILI) is the most common reason for withdrawal of anticancer drugs from the market. To prevent adverse side effects of drugs, it is important to investigate potential toxicity in vitro. However, outcome of cytotoxicity screenings can differ remarkably depending on the method used. We aimed to compare XTT, ATP-based CellTiter-Glo®2.0 and trypan blue exclusion (TBE) assays regarding their sensitivity in detecting acute cytotoxicity on HepG2 cells after incubation with the classical anticancer drugs Taxol and Imatinib or with the proteasome inhibitor MG-132. HepG2 cells were treated for 48 h and cell viability was analysed by XTT, CellTiter-Glo®2.0 or TBE assay. All tested compounds showed a reduction of viability of HepG2 cells. However, assay results differed significantly: Both ATP-based and TBE assay showed concentration-dependent cytotoxic effects, but outcomes were less pronounced with TBE. In contrast, the widely used XTT assay did not detect any acute cytotoxicity of Taxol and Imatinib. Acute cytotoxic effects of tested compounds could be revealed. However, results were significantly different from each other with ATP assay being the most sensitive one under the conditions tested. Thus, acute cytotoxicity can be dramatically underestimated if only standard XTT test is used.

Biocompatible, pH-responsive, and biodegradable polyurethanes as smart anti-cancer drug delivery carriers

In this study, biocompatible and biodegradable polyurethanes (PUs) were prepared by using different amino acids as chain extenders. Their structure and morphology were determined by fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis whereas their mechanical properties were evaluated by universal testing machine. These PUs were not only screened for their in vitro and in vivo cytotoxicity but also evaluated for their water uptake, swelling behavior, hydrolytic degradation and employed as pH-responsive drug delivery carriers. An anti-cancer drug imatinib was loaded to these PUs with 94% of loading efficiency and its release behavior was studied at different pH values. All the PUs showed a persistent local release for >300 h. The results exhibited that drug released at physiological pH (7.4) is far lesser as compared to the acidic and basic pH of the release media. At acidic pH, 82% of the drug has been released as compared to the 41% at physiological pH. The results clearly demonstrate that these PUs are safe and can be used as intelligent drug release matrices for targeted drug delivery.

Heterogeneity in the in vitro susceptibility of Loa loa microfilariae to drugs commonly used in parasitological infections

BackgroundCo-infection with loiasis remains a potential problem in control programs targeting filarial infections. The effects of many anti-parasitic drugs often administered to Loa loa infected people are not well documented. This study compared the in vitro activity of several of these drugs on the viability of L. loa microfilariae (mf).MethodsHuman strain L. loa mf were isolated from baboon blood using iso-osmotic Percoll gradient, and cultured in RPMI 1640/10% FBS with antimalarial drugs (mefloquine, amodiaquine, artesunate, chloroquine and quinine), anthelmintics (ivermectin, praziquantel, flubendazole and its reduced and hydrolyzed metabolites), two potential trypanocidal agents (fexinidazole and Scynexis-7158) and the anticancer drug imatinib. The drug concentrations used varied between 0.156 μg/ml and 10 μg/ml. Mf motility (CR50 = 50% immotility) and a metabolic viability assay (MTT) were used to assess the effects of these drugs on the parasites.ResultsMf in control cultures showed only a slight reduction in motility after 5 days of culture. Active inhibition of Loa loa motility was seen with mefloquine and amodiaquine (CR50 values of 3.87 and 4.05 μg/ml, respectively), immobilizing > 90% mf within the first 24 hours: mefloquine killed the mf after 24 hours of culture at concentrations ≥ 5 μg/ml. SCYX-7158 also induced a concentration-dependent reduction in mf motility, with > 50% reduction in mf motility seen after 5 days at 10 μg/ml. The anticancer drug imatinib reduced mf motility at 10 μg/ml from the first day of incubation to 55% by day 5, and the reduction in motility was concentration-dependent. Praziquantel and fexinidazole were inactive, and FLBZ and its metabolites, as well as ivermectin at concentrations > 5 μg/ml, had very minimal effects on mf motility over the first 4 days of culture.ConclusionsThe considerable action of the anti-malarial drugs mefloquine and amodiaquine on Loa mf in vitro highlights the possibility of repurposing the existing anti-infectious agents for the development of drugs against loiasis. The heterogeneity in the activity of anti-parasitic agents on Loa loa mf supports the need for further investigation using animal models of loiasis.

Recurrent Spindle Cell Carcinoma Shows Features of Mesenchymal Stem Cells

This study investigated a case of spindle cell carcinoma (SpCC) in tongue pathological lesions. The patient experienced a local recurrence and distant metastasis after surgical intervention. Although standard chemotherapy was administered, a granulomatous mass continued to develop. This aggressive growth led to survival of the tumor. Secondary debulking surgery was performed to improve the patient’s quality of life at the request of the patient. Using a tissue sample derived from the secondary debulking surgery, we performed an analysis of the tumor’s cell surface antigens, differentiation potential, metastatic ability, and inhibition potential by anticancer reagents. In vitro analysis revealed that the cell population grown under adherent culture conditions expressed the mesenchymal stem cell (MSC) markers CD73, CD90, and CD105. The cell line established from this SpCC contained colony-forming unit fibroblasts (CFU-Fs) and exhibited multipotent differentiation into several mesenchymal lineages, including bone, cartilage, and fat. The SpCC cells also displayed vigorous mobilization. These characteristics suggested that they had the differentiation potential of mesenchymal cells, especially MSCs, rather than that of epithelial cells. The surgical specimen analyzed in this study resisted the molecular target reagent cetuximab, which is an epidermal growth factor receptor inhibitor. This clinical insight revealed that chemotherapy-resistant SpCC cells have different characteristics compared to most other cancer cells, which are sensitive to cetuximab. Our cell death assay revealed that SpCC cell death was induced by the anticancer drug imatinib, which is known to inhibit protein tyrosine kinase activity of ABL, platelet-derived growth factor receptor α (PDGFRα), and KIT. Here, we report recurrent SpCC with characteristics of MSCs and potential for treatment with imatinib.

Cytotoxic activity of fucoxanthin, alone and in combination with the cancer drugs imatinib and doxorubicin, in CML cell lines

In the present study, we evaluate the in vitro cytotoxicity of fucoxanthin (Fx) on two human leukemia cell lines, K562 and TK6, alone and in combination with the conventional anticancer drugs imatinib (Imat) and doxorubicin (Dox). For the purpose, we assessed the cytotoxic and proliferation effects by cell count, induction of DNA damage by comet assay, and cell death by nuclear condensation, annexin V staining, coupled with propidium iodide uptake, and protein expression of Bax, caspase-3, and Bcl-2 (western blot). Our results show that Imat increased cytotoxicity in TK6 cells and inhibited proliferation in K562 cells, while Dox decreased cell viability and proliferation in both cell lines. Fx per se increased cytotoxicity against K562 cells and decreased cell proliferation of K562 and TK6 cells. The effects were confirmed by phase contrast microscopy. However, the antiproliferative effects are not explained by induction of DNA damage or cell death. In co-incubation, Fx increased antiproliferative effects of both drugs in the cell lines tested, however no differences where observed relative to Fx alone. This study unveiled in vitro cytotoxicity of Fx by inhibition of cell proliferation in both cell lines. Further studies are needed to elucidate the signal transduction pathways and molecular targets involved in that effect.

Anodic oxidation of anti-cancer drug Imatinib on different electrodes: Kinetics, transformation by-products and toxicity assessment

Degradation of anti-cancer drug Imatinib (IMT) in aqueous solution by anodic oxidation at different electrodes, namely Ti/RuO2, Ti/Pt, Ti/IrO2RuO2, Ti/Ta2O5SnO2IrO2, Ti/IrO2Ta2O5 SnO2/Pt and boron doped diamond (BDD), has been investigated. The effect of the applied current density and initial pH of the solution were examined. The electron structure calculations has been calculated by density functional theory (DFT). These results were compared to the results of liquid chromatography-mass spectroscopy (LC-MS-MS) and the metabolites has been identified. Moreover, the toxicity behavior of treated IMT solution by Ti/RuO2 and BDD electrodes were clarified and compared. IMT degradation was in the order of Ti/RuO2>Ti/Pt > Ti/IrO2Ta2O5>Ti/Ta2O5SnO2IrO2>Ti/IrO2RuO2>SnO2/Pt > BDD. At the initial stage of the IMT degradation, fragments with molecular weights 394 and 100 g mol−1 are formed. As a result of further degradation, the metabolites with m/z = 394 g mol−1 and m/z = 222 g mol−1 were formed. The bond NHC/O breakup may happen with the appearance of fragments having molecular weights 217 and 277 g mol−1. Experimental exploration of the metabolites has been also confirmed by the LC-MS-MS. EC50 value of IMT solution was determined as 2.50 mg L−1. Toxicity of BDD treated solution was significantly higher than Ti/RuO2 treated solution at the end of the process. This study demonstrates that anodic oxidation of IMT could be applied for the degradation of such anti-cancer drugs in wastewater treatment. Considering the toxicity behavior of treated IMT solutions, the usage of Ti/RuO2 as anode was the most effective one together with its oxidation capacity.

Photoactivation of imatinib–antibody conjugate using low-energy visible light from Ru(ii)-polypyridyl cages

Ru(ii)-polypyridyl cages with sterically bulky bidentate ligands provide efficient photochemical release of the anticancer drug imatinib using low energy visible light, imparting spatiotemporal control over drug bioavailability. The light-activated drug release is maintained when the Ru(ii) cage is covalently coupled to an antibody, which is expected to localize selectively on the tumor.

Exploring the binding of two potent anticancer drugs bosutinib and imatinib mesylate with bovine serum albumin: spectroscopic and molecular dynamic simulation studies.

Bosutinib (BST) and imatinib mesylate (IMT) are tyrosine kinase inhibitors (TKIs). In view of the importance of these inhibitors in cancer treatment, we investigated the mechanism of interaction between BST/IMT and bovine serum albumin (BSA) using various spectroscopic and molecular docking methods. Fluorescence studies indicated that BST/IMT interacted with BSA without affecting the microenvironment around the residue Trp213 of BSA. The quenching mechanism associated with the BST-BSA and IMT-BSA interactions was determined by performing fluorescence measurements at different temperatures. These results suggested that BST and IMT quenched the fluorescence intensity of BSA through static and dynamic processes, respectively, which was confirmed by time-resolved fluorescence measurements. Evaluation of the thermodynamic parameters ∆H°, ∆S°, and ∆G° suggested that hydrophobic and electrostatic interactions played significant roles in the BST-BSA interaction, while IMT-BSA was stabilized by hydrophobic forces. Competitive experimental results revealed that the primary binding sites for BST and IMT on BSA were sites II and I, respectively. This was supported by the results of molecular docking and dynamic simulation studies. The change in the secondary structure of BSA upon binding with BST/IMT was investigated by 3D fluorescence, absorption, and CD spectroscopic studies. In addition, the influences of β-cyclodextrin and metal ions (Cu2+ and Zn2+) on the binding affinities of BST and IMT to BSA were examined. Graphical abstract Binding of BST and IMT in BSA at site II and site I respectively.

A layer-by-layer sensing architecture based on dendrimer and ionic liquid supported reduced graphene oxide for simultaneous hollow-fiber solid phase microextraction and electrochemical determination of anti-cancer drug imatinib in biological samples

Electrochemical sensor for simultaneous microextraction and electrochemical determination of anticancer drug imatinib were developed by the dendrimer assisted reduced graphene oxide adsorbent. The steps of the method are as follows: Initially, the fabricated nanocomposite was deposited on the surface of the pencil graphite lead. Then the modified pencil graphite electrode carefully placed inside a piece of polypropylene hollow fiber using an ionic liquid as the carrier. The working electrode was used in conjunction with an auxiliary electrode, and a reference electrode in a three electrode system. The study was explored using the Taguchi experimental design method. For this purpose, the parameters including the type of dendrimer, dendrimer and reduced graphene oxide amounts, dendrimer to reduced graphene oxide ratio in hollow fiber and the sample solution pH, were optimized with a Taguchi L25 orthogonal array (OA) design. The results were confirmed by the ANOVA. Calibration curves were found to be linear in the range from 0.01 to 200μmolL−1, with two linear ranges, first from 0.01 to 10μmolL−1 and second from 10 to 200μmolL−1, with a detection limit of 7.39nmolL−1. The selectivity of the optimized procedure was examined in the presence of two anticancer drugs and some common excipients to monitor the interference effect. In addition, the comparison between hollow fiber-modified pencil graphite sensor and modified pencil graphite electrode demonstrated that the newly designed sensor showed that the fiber sensor offers a wider linear range, more sensitivity, and low detection limit.

The impact assessment of anticancer drug imatinib on the feeding behavior of rotifers with an integrated perspective: Exposure, post-exposure and re-exposure

The anticancer drugs are getting increasing attention as an emerging contaminant in the aquatic environments. In the present study, feeding behavior of the rotifer Brachionus calyciflorus under the impact of anticancer drug imatinib was evaluated. Traditional toxicological studies usually focus on dose-effect relationship at a given exposure time, while ignore the possible impact after the exposure. Thus, how the impact varied in the post-exposure and re-exposure was also considered in the present study. The feeding depression of the rotifers was attributed to the increased concentration of imatinib. Although the filtration and ingestion rate of the rotifers recovered to a certain extent after the exposure, the significant feeding inhibition still persisted even if the exposure was ended. In the re-exposure period, the feeding behavior was less depressed than those of the exposure period, which implied that rotifers might develop a tolerance to the same toxics. The activities of acetylcholine esterase (AchE) and the levels of reactive oxygen species (ROS) in rotifers were also detected. Imatinib inhibited the activities of AchE in the exposure and re-exposure while ROS levels increased significantly in the re-exposure period. Our present study provided an integrated assessment the potential environmental risks of imatinib at a new perspective.