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A lot of solid tumors are characterized by uncontrolled signal transduction triggered by receptors related to cellular growth. The targeting of these cell receptors with antitumor drugs is essential to improve chemotherapy efficacy. This can be achieved by conjugation of an active targeting agent to the polymer portion of a colloidal drug delivery system loaded with an antitumor drug. The goal of this minireview is to report and discuss some recent results in epidermal growth factor receptor targeting by the GE11 peptide combined with colloidal drug delivery systems as smart carriers for antitumor drugs. The minireview chapters will focus on explaining and discussing: (i) Epidermal growth factor receptor (EGFR) structures and functions; (ii) GE11 structure and biologic activity; (iii) examples of GE11 conjugation and GE11-conjugated drug delivery systems. The rationale is to contribute in gathering information on the topic of active targeting to tumors. A case study is introduced, involving research on tumor cell targeting by the GE11 peptide combined with polymer nanoparticles.

Tumors are a major cause of human mortality worldwide, and the rapid development of nanomaterials (NMs) for tumor therapy and drug delivery has provided new treatment methods. However, NMs' high immunogenicity, short circulation time, and low specificity limit their application in tumor therapy. In recent years, bionanomaterials using cell membranes have emerged to overcome the shortcomings of monomeric NMs. Cell membrane-encapsulated NMs extracted from multiple cells not only retain the physicochemical properties of NMs but also inherit the biological functions of the source cells, aiding in drug delivery. The combination of the cell membrane and drug-loading NMs offers an efficient and targeted drug delivery system tailored to the tumor microenvironment. The research and application of this method have been widely carried out in the academic field of tumor diagnosis and treatment. This review presents the recent research progress of cell membrane-coated NMs as drug carriers in tumor therapy, including cell membrane extraction methods, encapsulation strategies, and the applications of cell membrane-encapsulated NMs in tumor therapy. We believe that biomimetic nanomaterials will be a promising and novel anticancer strategy in the future, and their wide application will certainly bring vitality to the field of tumor diagnosis and treatment. The combination of membrane and drug-loading nanomaterials embodies a highly efficient and target drug delivery system tailored to the tumor microenvironment, which broadens a new path of drug delivery for future cancer treatment. Meanwhile, it is also a perfect combination and application of biomedical nanomaterials, which is of great significance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The experiments here reported evidence on the importance of the residual charge of a nucleotide derivative, for the adsorption on nHAP (hydroxyapatite nanocrystals), in water solution. We found that the simple presence of phosphates on the nucleotide derivative does not guarantee adsorption on nHAP. On the other hand, we demonstrated that a cationic or neutral charge on a nucleotide derivative produces a strongly reduced chemical adsorption (chemisorption) whereas, in the presence of a net negative charge, relevant adsorption on nHAP is observed. The number of phosphates can only modulate the adsorption efficiency of a molecule provided that this latter bears an overall negative charge. The neutral zwitterionic nucleotide Pt(II) complexes, bearing negatively charged phosphates, are unable to give stable chemisorption. Previous considerations are important to model the binding ability of phosphate bearing nucleotide derivatives or molecules on hydroxyapatite. The findings reported in the present paper could be relevant in bone tissue targeting or nHAP mediated drug delivery. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two novel 2-nitroimidazole-naphthalimide-derived antitumor agents N -(2-(naphthalimide)ethyl)-2-(2-nitroimidazole)acetamide (D-2) and N -(2-(5-nitro-naphthalimide)ethyl)-2-(2-nitroimidazole) acetamide (D-5) were synthesized. • The redox mechanisms of D-2 and D-5 were studied to provide reference for clinical trials. • D-2 and D-5 could intercalate into DNA with a high affinity and cause the oxidative damage. • D-2 and D-5 were proved to have significantly better cell selectivity than mitonafide. In this work, we designed and synthesized two novel 2-nitroimidazole-naphthalimide-derived antitumor agents N -(2-(naphthalimide)ethyl)-2-(2-nitroimidazole)acetamide (D-2) and N -(2-(5-nitro-naphthalimide)ethyl)-2-(2-nitroimidazole)acetamide (D-5). The oxidative damage induced by the interaction between D-2 (D-5) and DNA was investigated by CV and DPV. The efficient electrochemical biosensors were prepared through modifying GCE with calf thymus DNA, poly dA and poly dG, respectively. The redox mechanism of D-2 (D-5) on GCE surface involved the reduction of 2-nitro group on imidazole ring and the oxidation of methylene linked naphthalimide skeleton and 2-nitroimidazole. The results of voltametric evaluation of interaction between antitumor agent and DNA/GCE revealed the oxidative damage of DNA caused by D-2 (D-5). In addition, UV–vis absorption and fluorescence spectra were investigated to further distinguish the interaction mode between D-2 (D-5) and DNA, implying the intercalation mode of D-2 (D-5) toward base pairs of DNA with a high affinity. At last, D-2 and D-5 were proved to have significantly better cell selectivity than mitonafide, the fact indicated that D-2 and D-5 had the potential for becoming lead antitumor agents and eliminating the side effects toward normal cells. [ABSTRACT FROM AUTHOR]

Although chemotherapeutic drugs are widely applied for clinic tumor treatment, severe toxicity restricts their therapeutic efficacy. In this study, we reported a new form of selenium, selenium nanoparticles (Nano Se) which have significant lower toxicity and acceptable bioavailability. We investigated Nano Se as chemotherapy preventive agent to protect against toxicities of anticancer drug irinotecan and synergistically enhance the anti-tumor treatment effect in vitro and in vivo . The underlying mechanisms were also investigated. The combination of Nano Se and irinotecan showed increased cytotoxic effect with HCT-8 tumor cells likely by p53 mediated apoptosis. Nano Se inhibited growth of HCT-8 tumor cells partially through caspases mediated apoptosis. In vivo experiment showed Nano Se at a dose of 4 mg/kg/day significantly alleviated adverse effects induced by irinotecan (60 mg/kg) treatment. Nano Se alone treatment did not induce any toxic manifestations. The combination of Nano Se and irinotecan dramatically inhibited tumor growth and significantly induced apoptosis of tumor cells in HCT-8 cells xenografted tumor. Tumor inhibition rate was about 17.2%, 48.6% and 62.1% for Nano Se, irinotecan and the combination of Nano Se and irinotecan, respectively. The beneficial effects of Nano Se for tumor therapy were mainly ascribed to selectively regulating Nrf2-ARE (antioxidant responsive elements) pathway in tumor tissues and normal tissues. Our results suggest Nano Se is a promising selenium species with potential application in cancer treatment. [ABSTRACT FROM AUTHOR]

Polynuclear platinum complexes constitute a special class of hopeful antitumor agents. In this study, a Y-type monofunctional trinuclear platinum complex (MTPC) with 1,3,5-tris(pyridin-2-ylmethoxy)benzene, ammine and chloride as ligands was synthesized and characterized by ¹H NMR and electrospray ionization mass spectrometry (ESI-MS). The DNA binding mode of MTPC was investigated using circular dichroism spectroscopy and gel electrophoresis, and the reactivity of MTPC towards glutathione was studied by ¹H NMR and ESI-MS. The results show that MTPC can affect the conformation of calf-thymus DNA (CT-DNA) significantly and tends to form 1,4-GG rather than 1,2-GG intrastrand crosslinks, which are different from the instance of cisplatin. MTPC reacts with glutathione quite slowly in comparison with cisplatin because of the steric hindrance. The cytotoxicity of MTPC was tested on the human breast cancer cell line MCF-7, the human non-small-cell lung cancer cell line A549, and the human ovarian cancer cell line Skov-3 by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. MTPC is more potent than or comparable to cisplatin. The cellular inhibition mode of MTPC was examined by flow cytometry using MCF-7 cells. MTPC arrests the cell cycle mainly in G2 or M phase, while cisplatin arrests the cell cycle in S phase. Similar to cisplatin, MTPC kills the cells predominantly through an apoptotic pathway. [ABSTRACT FROM AUTHOR]

Triptolide is a traditional Chinese medicinal herb-derived antineoplastic agent. However, its antitumor activity against gynecologic carcinomas has not yet been well described. It is the purpose of this article to investigate the effect and mechanism of triptolide in human ovarian cancer using both A2780 (p53 wild) and OVCAR-3 (p53 mutated) cells. Our results showed that triptolide exerted a potent inhibitory effect on the growth and proliferation of both cell lines in a dose- and time-dependent manner and that the effect was independent of the expression of p53. In contrast, triptolide had only a marginal cytotoxicity in noncancerous ovary cells, lung fibroblast cells, and macrophage cells, indicating differential inhibitory effects of the drug on cell growth between ovarian cancer cells and normal tissue cells. Exposure of the ovarian cancer cells to triptolide induced apoptosis, as evaluated by annexin V/propidium iodide-labeled flow cytometry. Triptolide-induced apoptosis was accompanied by cytochrome c release and caspase-3 activation and was associated with downregulation of Bcl-2 and upregulation of Bax. Cell cycle analysis demonstrated that treatment with triptolide induced cell cycle S phase arrest in A2780 cells and G2/M phase arrest in OVCAR-3 cells. Further detection by Western blotting revealed that the cell cycle arrest by triptolide in both cell lines occurred in concert with increased expression of p21. This study shows that triptolide selectively kills ovarian cancer cells with different p53 status predominantly through regulating the coordinate and dynamic cellular processes of proliferation and apoptosis, thereby making it a promising chemotherapeutic agent against a broad spectrum of ovarian carcinomas. [ABSTRACT FROM AUTHOR]

Two novel polymer-drug conjugates norcantharidin-poly(vinyl alcohol) and norcantharidin-chitosan (NCTD-PVA and NCTD-CS) were synthesized via alcoholysis reaction and characterized by 1H-NMR and FTIR. NCTD was released from the conjugates via hydrolysis, faster in PBS (pH 5.0) than that in PBS (pH 7.4). NCTD-PVA and NCTD-CS inhibited human esophageal carcinoma ECA-109 cell and murine breast cancer EMT6 cell growth in a dose-dependent manner. The IC50 values of NCTD, NCTD-PVA and NCTD-CS on ECA-109 cell at 48 h were 9.4 ± 0.9, 55.3 ± 3.0 and 168.8 ± 8.9 μg/ml, respectively, and the IC50 values of the three compounds on EMT6 cell were 3.1 ± 0.3, 30.5 ± 5.4 and 90.7 ± 8.1 μg/ml, respectively. The two conjugates both induced esophageal carcinoma ECA-109 cell apoptosis and arrested cell cycle at the S phase. Caspase-8 and caspase-3 were activated in the ECA-109 cell after incubating with NCTD-PVA or NCTD-CS. The primary in vivo antitumor activity was assessed in the EMT6 tumor-bearing mouse model. NCTD-PVA and NCTD-CS displayed higher tumor inhibition rates than that of free NCTD. [ABSTRACT FROM AUTHOR]

A series of drug delivery systems based on a sodium alginate derivative were prepared by mixing glycyrrhetinic acid (GA) and doxorubicin (DOX) conjugates at different ratios. GA (a liver-targeting ligand) and DOX (an antitumor drug) were both conjugated to oligomeric glycol monomethyl ether-modified sodium alginate (ALG-mOEG) for prolonged duration of action. These NP-based delivery systems exhibited active cell uptake and cytotoxicity in vitro and liver-targeted distribution and anti-tumor activity in vivo. In addition, nanoparticles with a 1:1 ( W: W) ratio of GA-ALG-mOEG and DOXALG-mOEG (NPs-3) showed the highest cellular uptake and cytotoxicity in vitro and liver-targeted distribution and antitumor activity in vivo. Specifically, when mixed nanoparticles defined as NPs-3 were injected in mice, liver DOX concentration reached 61.9 μg/g 3 h after injection, and AUC and t of DOX in liver reached 4744.9 μg·h/g and 49.5 h, respectively. In addition, mice receiving a single injection of NPs-3 exhibited much slower tumor growth (88.37% reduction in tumor weight) 16 days after injection compared with placebo. These results indicate that effective cancer treatment may be developed using mixed NP delivery systems with appropriate ratio of targeted ligand and drug. [ABSTRACT FROM AUTHOR]

Although the clinical application of nanoparticles is still limited by biological barriers and distribution, with the deepening of our understanding of nanoparticles over the past decades, people are gradually breaking through the previous limitations in the diagnosis and treatment of tumors, providing novel strategies for clinical decision makers. The transition of nanoparticles from passive targeting to active tumor-targeting by abundant surface-modified nanoparticles is also a development process of precision cancer treatment. Different particles can be used as targeted delivery tools of antitumor drugs. The mechanism of gold nanoparticles inducing apoptosis and cycle arrest of tumor cells has been discovered. Moreover, the unique photothermal effect of gold nanoparticles may be widely used in tumor therapy in the future, with less side effects on surrounding tissues. Lipid-based nanoparticles are expected to overcome the blood-brain barrier due to their special characteristics, while polymer-based nanoparticles show better biocompatibility and lower toxicity. In this paper, we discuss the development of nanoparticles in tumor therapy and the challenges that need to be addressed.

Context: Lung cancer, the most common type of cancer, has a high mortality rate. Cucurbitacin B (CuB), a natural compound extracted from Cucurbitaceae plants, has antitumor effects., Objective: We investigated the role of CuB on lung cancer and its potential mechanisms., Materials and Methods: A549 cells were treated with 0.1, 0.3, 0.6, and 0.9 μM CuB for 12, 24, and 48 h or untreated. Gene and protein levels were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Enzyme-linked immunosorbent assay (ELISA) detected inflammatory factors levels (TNF-α and IL-10). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and colony formation assays measured cell viability, apoptosis, and proliferation. The interaction between miR-let-7c and long non-coding RNA X inactive-specific transcript (XIST) or interleukin-6 (IL-6) was verified by dual-luciferase reporter assays., Results: CuB treatment inhibited the proliferation of lung cancer cells and promoted cell apoptosis, and increased the expression of Bax and cleaved caspase3, decreased cyclin B1 and Bcl-2 expression. CuB suppressed XIST and IL-6 expression, and enhanced miR-let-7c expression. XIST silencing enhanced the inhibitory effect of CuB on cell proliferation and the promotion effect on apoptosis via upregulating miR-let-7c. Moreover, XIST targeted miR-let-7c to activate the IL-6/STAT axis. MiR-let-7c overexpression enhanced the regulatory effect of CuB on proliferation and apoptosis via suppressing the IL-6/STAT3 pathway., Discussion and Conclusion: CuB regulated cell proliferation and apoptosis by inhibiting the XIST/miR-let-7c/IL-6/STAT3 axis in lung cancer. These findings indicate CuB may have the possibility of clinical application in lung cancer treatment.

Abstract: We investigated the incorporation of gemcitabine into a colloidal carrier based on the biodegradable and biocompatible poly(d,l-lactide-co-glycolide) (PLGA) to optimize its anticancer activity. Two synthesis techniques (double emulsion/solvent evaporation, and Flow Focusing®) were compared in terms of particle geometry, electrophoretic properties (surface charge), gemcitabine vehiculization capabilities (drug loading and release), blood compatibility, and in vitro antitumor activity. To the best of our knowledge, the second formulation methodology (Flow Focusing®) has never been applied to the synthesis of gemcitabine-loaded PLGA particles. With the aim of achieving the finest (nano)formulation, experimental parameters associated to these preparation procedures were analyzed. The electrokinetics of the particles suggested that the chemotherapy agent was incorporated into the polymeric matrix. Blood compatibility was demonstrated in vitro. Flow Focusing® led to a more appropriate geometry, higher gemcitabine loading and a sustained release profile. In addition, the cytotoxicity of gemcitabine-loaded particles prepared by Flow Focusing® was tested in MCF-7 human breast adenocarcinoma cells, showing significantly greater antitumor activity compared to the free drug and to the gemcitabine-loaded particles synthesized by double emulsion/solvent evaporation. Thus, it has been identified the more adequate formulation conditions in the engineering of gemcitabine-loaded PLGA nanoparticles for the effective treatment of tumours. [Copyright &y& Elsevier]

Abstract: Introduction: Sepantronium bromide (YM155) is an antitumor drug in development and is a first-in-class chemical entity, which is a survivin suppressant. We developed a radiosynthesis of [11C]YM155 to non-invasively evaluate its tissue and tumor distribution in mice bearing human prostate tumor xenografts. Methods: Methods utilizing [11C]acetyl chloride and [11C]methyl triflate, both accessible with automated radiosynthesis boxes, were evaluated. The O-methylation of ethanolamine-alkolate with [11C]methyl triflate proved to be the key development toward a rapid and efficient process. The whole-body distribution of [11C]YM155 in PC-3 xenografted mice was examined using a planar positron imaging system (PPIS). Results: Sufficient quantities of radiopharmaceutical grade [11C]YM155 were produced for our PET imaging and distribution studies. The decay corrected (EOB) radiochemical yield was 16–22%, within a synthesis time of 47min. The radiochemical purity was higher than 99%, and the specific activity was 29–60GBq/μmol (EOS). High uptake levels of radioactivity (%ID/g, mean±SE) were observed in tumor (0.0613±0.0056), kidneys (0.0513±0.0092), liver (0.0368±0.0043) and cecum (0.0623±0.0070). The highest tumor uptake was observed at an early time point (from 10min after) following injection. Tumor-to-blood and tumor-to-muscle uptake ratios of [11C]YM155, at 40min after injection, were 26.5 (±2.9) and 25.6 (±3.6), respectively. Conclusion: A rapid method for producing a radiopharmaceutical grade [11C]YM155 was developed. An in vivo distribution study using PPIS showed high uptake of [11C]YM155 in tumor tissue. Our methodology may facilitate the evaluation and prediction of response to YM155, when given as an anti-cancer agent. [Copyright &y& Elsevier]

Ferroptosis is a form of non-apoptotic and iron-dependent cell death originally identified in cancer cells. Recently, emerging evidence showed that ferroptosis-targeting therapy could be a novel promising anti-tumour treatment. However, systematic analyses of ferroptosis-related genes for the prognosis of non-small cell lung cancer (NSCLC) and the development of antitumor drugs exploiting the ferroptosis process remain rare. This study aimed to identify genes related to ferroptosis and NSCLC and to initially screen lead compounds that induce ferroptosis in tumor cells. We downloaded mRNA expression profiles and NSCLC clinical data from The Cancer Genome Atlas database to explore the prognostic role of ferroptosis-related genes. Four prognosis-associated ferroptosis-related genes were screened using univariate Cox regression analysis and the lasso Cox regression analysis, which could divide patients with NSCLC into high- and low-risk groups. Then, based on differentially expressed risk- and ferroptosis-related genes, the negatively correlated lead compound flufenamic acid (FFA) was screened through the Connective Map database. This project confirmed that FFA induced ferroptosis in A549 cells and inhibited growth and migration in a dose-dependent manner through CCK-8, scratch, and immunofluorescence assays. In conclusion, targeting ferroptosis might be a therapeutic alternative for NSCLC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Cui, Zhang, Guo, Deng, Wen, Lu, Shi, Xing, Liu and Zhang.)

Abstract: We synthesized 47 kinds of 3-amino- or 3-benzylamino-β-carboline derivatives with a substituent on the 6-, 8-, or 6,8-carbon atoms and evaluated their antitumor activities for Hela S-3 and Sarcoma 180 cell lines using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Consequently, we succeeded to develop 3-benzylamino-8-methylamino-β-carboline (17a) and 8-methylamino-3-(3-phenoxybenzyl)amino-β-carboline (17c) with antitumor activity with IC50 values of 0.046, 0.032μM, respectively, against HeLa S-3 cell line, which are higher than that of previously reported 3-(3-phenoxybenzyl)amino-β-carboline (10e) of 0.074μM. Furthermore, effects of Cl group at 6-carbon atom on the type of cell death was evaluated using 3-benzylamino-6-chloro-β-carboline (10b), 3-benzylamino-β-carboline (10d), N-(3-benzylamino)-6-chloro-9H-β-carbolin-8-yl)benzamide (14g), and N-(3-benzylamino-9H-β-carbolin-8-yl)benzamide (17b) to show no effect. Hoechst 33342 staining and DNA fragmentation assay suggested that these compounds induced cell death by apoptosis. In addition, using flow cytometry analysis, we established that the cell death pathway was through the arrest of the cell cycle in the G2/M phase. [Copyright &y& Elsevier]

Abstract: This paper presents TGI-Simulator, a software tool designed to show, through a 2-D graphical animation, the simulated time effect of an anticancer drug on a tumor mass by exploiting the well-known Tumor Growth Inhibition (TGI) model published by Simeoni et al. . Simeoni TGI model is a mathematical model routinely used by pharma companies and researchers during the drug development process. The application is based on a Java graphical user interface (GUI) including a self installing differential equation solver implemented in Matlab together with an optimization algorithm that performs model identification via Weighted Least Squares (WLS). However, it can graphically show also the simulation results obtained within other scientific software tools, if they are preventively stored into a suitable ASCII file. The tool would be a valid support also for researchers with no specific skills in scientific calculations and in pharmacokinetic and pharmacodynamic modeling but daily involved in pharma companies drug development processes at different levels. The availability of a movie with a temporal varying 2-D iconographic representation is an original instrument to communicate results and learn Simeoni TGI model and its potential application in preclinical studies. [Copyright &y& Elsevier]

Abstract: Cancer accounted for huge number of deaths, which represents about 13% of all deaths worldwide, and the number of the deaths due to cancer is increasing. Natural products and their synthetic analogs are widely used as antitumor drugs. As represented by these drugs, many anticancer drugs originated from cytotoxic compounds. Marine natural products are a gold mine of strong bioactive compounds with unique structures created in evolution of organisms over hundred million years. However, in the field of drug discovery, most studies have focused on plant essences and bacterial metabolites, and candidate compounds from marine origin are still remaining relatively unexplored. [Copyright &y& Elsevier]

Abstract: 3-(3-Phenoxybenzyl)amino-β-carboline 2h showed extremely-high activity; the IC50 value was 0.074μM. To verify 2h-induced cell death types, we observed the chromatin condensation, the DNA fragmentation and activated caspase-3 using Hoechst 33342, agarose electrophoresis and western blot, and suggesting 2h-induced cell death type was apoptosis. Flow cytometry showed that 2h-treated cell was induced SubG1 cell population after G2/M cell cycle arrest. In addition, using affinity chromatography and peptide mass fingerprinting, we found that interacting protein with this compound was α-tubulin protein. [Copyright &y& Elsevier]

Abstract: Drug-induced acute pancreatitis (DAP) is defined as pancreatitis with corresponding clinical manifestations resulted from drug-induced pancreatic secretion dysfunction and pancreatic tissue damage. One case of DAP resulted from chemotherapeutics (Nimustine) was diagnosed and treated our in hospital in 2009. This patient belonged to pancreatitis induced by anticancer drugs, and the toxicity of anticancer drugs acted directly on pancreatic cells, leading to the occurrence of pancreatitis. After treatment, the pancreatitis was effectively treated in this patient, but the final the patient and his family eventually gave up the treatment due to aggravated primary diseases. [ABSTRACT FROM AUTHOR]

Abstract: The molecular structure and vibrational frequencies of cis-[Pt(CH3CN)2Cl2] were calculated by five density functional theory (DFT) and HF methods using several basis sets. The theoretical results are discussed and compared with the experimental data. It is remarkable that mPW1PW91 and PBE1PBE methods at SDD basis sets are clearly superior to the remaining density functional methods in predicting the structures of cis-[Pt(CH3CN)2Cl2]. Mean deviation between the calculated harmonic and observed fundamental vibrational frequencies for each method is also calculated. The results indicate that mPW1PW91 and PBE1PBE methods at SDD basis sets are also the best to predict vibrational spectra of cis-[Pt(CH3CN)2Cl2]. [ABSTRACT FROM AUTHOR]

Formerly by in vitro EPR spin-trapping technique we have demonstrated that nitroxyl free radical containing (spin-labeled) nitrosoureas 1-ethyl-1-nitroso-3-[4-(2,2,6,6-tetramethylpiperidine-1- oxyl)]-urea (SLENU) and N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-glycine amid of 2,2,6,6- tetramethyl-4-aminopiperidine-1-oxyl (SLCNUgly) possessed excellent superoxide anion scavenging activity (SSA). The aim of the present study was to investigate generation of lipid radicals in liver and kidney tissues of mice treated by SLENU or SLCNUgly, by EPR spin-trapping technique. N-tert-butyl-alpha-penylnitrone (PBN) was used as a spin-trapping agent. The higher levels of lipid radicals in both kind of tissues were registered in mice treated by SLCNUgly comparing to those of the controls and mice treated by SLENU. Based on these preliminary EPR spectroscopy results it might be concluded that the lower levels of lipid radicals generated in livers and kidneys of mice treated by SLENU might be explained by its slight alkylating activity when is compared to that of the other spin labeled nitrosourea SLCNUgly. [ABSTRACT FROM AUTHOR]

Background: Despite the very efficient antitumor activity of conventional chemotherapy, generally high doses of anticancer molecules must be administered to obtain the required therapeutic action, simultaneously leading to severe side effects. This is frequently a consequence of the development of multidrug resistance by cancer cells and of the poor pharmacokinetic profile of these agents. Objective: In Order to improve the antitumor effect of tegafur and overcome their important drawbacks, we have investigated its incorporation into a drug nanoplatform based on the biodegradable polymer chitosan. Materials and Methods: Two tegafur loading methods were studied: (i) absorption into the polymeric network (entrapment procedure); and (ii) surface deposition (adsorption procedure) in already formed chitosan nanoparticles. Results: Tegafur entrapment into the polymeric matrix has yielded higher drug loading values and a slower drug release profile, compared to single surface adsorption. The main factores determining the drug loading to chitosan were identified. Discussion and Conclusion: Such polymeric colloid present very interesting properties for efficient tegafur delivery to cancer. [ABSTRACT FROM AUTHOR]

An aromatic fatty acid, phenylacetate (PA), has been shown to have cytostatic, antitumor and cell differentiation-inducing effects on various kinds of tumors. Previously, we have demonstrated cell growth inhibition, malignant phenotype reduction and cell differentiation effects of sodium phenylacetate (NaPA) treatment in a canine mammary tumor cell line. To clarify the molecular mechanism of these effects, we examined the expression of Ras/MAPK signaling pathway-related molecules in human and canine breast cancer cell lines, and found that the level of c-Raf-1 protein was reduced by 5, 10 and 20 mM of NaPA treatments, though Ras activation was maintained. Dephosphorylation of c-Raf-1 at Serine (Ser) 259, Ser 338, and Ser 621 were also seen in NaPA-treated cells. Downstream factors in the pathway, such as mitogen-activated protein kinase/ERK kinase (MEK)1/2 and ERK1/2, showed decreased activity, and accordingly, expressions of cyclinD1, c-myc, and inactivation of p90 ribosomal S6 kinase (RSK), which are MAPK targets, were reduced. We also observed the reduction of cell-cycle-promoted molecules, such as cdc1/cdk2, cdk4, PCNA cyclin A, and cyclin B, and the increased expression of p27kip1. Furthermore, expression of an epithelial marker, E-cadherin, was increased by NaPA treatment. These results suggest that one of the molecular targets of NaPA treatment was the reduction of c-Raf-1 protein, and that its reduction results in the decrease of malignant characteristics of tumor cells through blockage of the Ras/MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Density functional theory (DFT), Hartree–Fock (HF) and Möller–Plesset second order perturbation (MP2) calculations were applied to study the mechanism of the two-step substitution reaction of cis-[Pt(en)(H2O)2]2+ (en=ethylenediamine) and thiourea. Pentacoordinated platinum transition state (TS) geometries for both steps of the title SN2 reaction were fully optimized at HF, B3LYP and MPW1PW91 levels of calculations. Distorted trigonal-bipyramidal TS’s with rather small entering ligand to metal to leaving ligand angles (≈800) and with prolonged bonds to the leaving and entering ligands (R Pt O ≈2.4Å and R Pt S ≈2.85Å) were investigated in this paper. Natural bond orbital (NBO) analysis method was performed for the investigation of major stabilizing orbital interactions. The self-consistent reaction field (SCRF) methods were used to study the reaction in liquid phase. Both steps of the reaction are exothermic and the computed activation enthalpy (ΔH ‡) and entropy (ΔS ‡) in the rate-determining steps (RI→TS→PI) are in good agreement with the experimental results. Thorough study of the reaction for improved values of energies and activation parameters was carried out at PCM/MP2 and PCM/B3LYP levels using 6-311+(d,p) and 6-311++(2d,2p) basis sets. The structural and activation parameters of the reaction suggest an associative interchange (I a) substitution mechanism. [Copyright &y& Elsevier]

Cellular uptake of platinum-based antitumor drugs is a critical step in the mechanism of the drug action and associated resistance, and deeper understanding of this step may inspire development of novel methods for new drugs with reduced resistance. Human copper transporter 1 (hCtr1), a copper influx protein, was recently found to facilitate the cellular entry of several platinum drugs. In the work reported here, we constructed a Met- and His-rich 20mer peptide (hCtr1-N20) corresponding to the N-terminal domain of hCtr1, which is the essential domain of hCtr1 for transporting platinum drugs. The interactions of the peptide with cisplatin and its analogues, including transplatin, carboplatin, oxaliplatin, and [Pt( l-Met)Cl2], were explored at the molecular level. Electrospray ionization (ESI) mass spectrometry (MS) data revealed that all of the platinum(II) complexes used in present study can bind to hCtr1-N20 in 1:1 and 2:1 stoichiometry. Four Met residues should be involved in binding to cis-platinum complexes on the basis of the tandem MS spectrometry and previously reported data. Time-dependent 2D [1H,15N] heteronuclear single quantum coherence NMR spectra indicate the reaction of cisplatin with hCtr1-N20 is a stepwise process. The intermediate, however, is transient, which is consistent with the ESI-MS results. Time-dependent ESI-MS data revealed that the geometry and the properties of both the leaving and the nonleaving groups of platinum(II) complexes play essential roles in controlling the reactivity and formation of the final products with hCtr1-N20. [ABSTRACT FROM AUTHOR]

Abstract: The protein tyrosine kinases (PTKs) are essential enzymes in cellular signaling processes that regulate cell growth, differentiation, migration and metabolism. Their inhibition was recently shown to constitute a new modality for treating cancers. Two clinically used PTK inhibitors (PTKIs), imatinib (Glivec™/Gleevec™) and nilotinib (Tasigna™) were investigated for their effects on the zinc enzymes carbonic anhydrases (CAs, EC 4.2.1.1). The two PTKIs inhibited all 13 catalytically active mammalian isoforms CA I–XV with K Is in the range of 4.1nM–20.2μM. CA I and CA II were the most potently inhibited isoforms (K Is of 4–32nM), whereas CA VA and VB showed the lowest affinity for these drugs (K Is of 5.4–20.2μM). In cancer cells, these inhibitors may interact with CAs in addition to the targets for which they were designed, the PTKs. [Copyright &y& Elsevier]

Cancer cells in hypoxic areas of solid tumors are to a large extent protected against the action of radiation as well as many chemotherapeutic drugs. There are, however, two different aspects of the problem caused by tumor hypoxia when cancer therapy is concerned: One is due to the chemical reactions that molecular oxygen enters into therapeutically targeted cells. This results in a direct chemical protection against therapy by the hypoxic microenvironment, which has little to do with cellular biological regulatory processes. This part of the protective effect of hypoxia has been known for more than half a century and has been studied extensively. However, in recent years there has been more focus on the other aspect of hypoxia, namely the effect of this microenvironmental condition on selecting cells with certain genetic prerequisites that are negative with respect to patient prognosis. There are adaptive mechanisms, where hypoxia induces regulatory cascades in cells resulting in a changed metabolism or changes in extracellular signaling. These processes may lead to changes in cellular intrinsic sensitivity to treatment irrespective of oxygenation and, furthermore, may also have consequences for tissue organization. Thus, the adaptive mechanisms induced by hypoxia itself may have a selective effect on cells, with a fine-tuned protection against damage and stress of many kinds. It therefore could be that the adaptive mechanisms may take advantage of for new tumor labeling/imaging and treatment strategies. One of the Achilles' heels of hypoxia research has always been the exact measurements of tissue oxygenation as well as the control of oxygenation in biological tumor models. Thus, development of technology that can ease this control is vital in order to study mechanisms and perform drug development under relevant conditions. An integrated EU Framework project 2004-2009, termed EUROXY, demonstrates several pathways involved in transcription and translation control of the hypoxic cell phenotype and evidence of cross-talk with responses to pH and redox changes. The carbonic anhydrase isoenzyme CA IX was selected for further studies due to its expression on the surface of many types of hypoxic tumors. The effort has led to marketable culture flasks with sensors and incubation equipment, and the synthesis of new drug candidates against new molecular targets. New labeling/imaging methods for cancer diagnosing and imaging of hypoxic cancer tissue are now being tested in xenograft models and are also in early clinical testing, while new potential anti-cancer drugs are undergoing tests using xenografted tumor cancers. The present article describes the above results in individual consortium partner presentations. [ABSTRACT FROM AUTHOR]

Abstract: 5-Fluorouracil (5-FU) is an antimetabolite with a broad-spectrum activity against solid tumors. However, its very short half-life in plasma circulation greatly limited the in vivo antitumor efficacy and clinical application. The current work aimed to solve this problem as well as to increase 5-FU biodistribution to tumor by covalently conjugating 5-FU to a biocompatible, non-toxic and non-immunogenic drug carrier –N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer. The in vitro cytotoxicity, in vivo biodistribution and therapeutic efficacy of HPMA copolymer–5-FU conjugates (P-FU) were reported. Cytotoxicity was evaluated by using a serial of tumor cells (A549, CT-26, Hela, HepG2 cells and 5-FU resistant HepG2 cells). In vivo biodistribution and therapeutic efficacy were investigated in Kunming mice-bearing hepatoma 22 (H22). Results indicated that P-FU could increase the cytotoxicity of 5-FU in Hela, HepG2 and 5-FU resistant HepG2 cells, while it decreases the cytotoxicity of 5-FU in A549 and CT-26. Both in vitro release profile in plasma and biodistribution study showed that P-FU significantly prolonged the drug plasma circulation time. P-FU also showed an over 3-fold larger area under the concentration–time curve (AUC) in tumor when compared with free drug. Therapeutic evaluation also demonstrated that the treatment with P-FU displayed stronger inhibition of the tumor growth when compared with that of control group (physiologic saline) or 5-FU group at the same dose. All the results suggested that P-FU could increase cytotoxicity of 5-FU in certain cancer cell lines, prolong 5-FU circulation time in vivo, enhance 5-FU distribution to tumor and improve therapeutic efficacy. Therefore, HPMA copolymer is a potential carrier for 5-FU for the effective treatment of cancer. [Copyright &y& Elsevier]

New antitumor active polymers, poly(methacryloyl-2-oxy-1,2,3-propanetricarboxylic acid- co-exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic acid) [poly(MTCA- co-ETAc)], poly(methacryloyl-2-oxy-1,2,3-propanetricarboxylic acid- co-hydrogen ethyl- exo-3,6-epoxy-1,2,3,6-tetrahydrophthalate) [poly(MTCA- co-HEET)], and poly (methacryloyl-2-oxy-1,2,3-propanetricarboxylic acid-co-a-ethoxy-exo-3,6-epoxy-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil) [poly(MTCA-co-EETFU)] were synthesized and characterized. Their antitumor activity, inhibition of DNA replication and antiangiogenesis were examined. The structures of the polymers were identified by FT-IR,H andC-NMR spectroscopy. The number average molecular weights of the fractionated polymers determined by GPC ranged from 9,400 to 14,900, and polydispersity indices were less than 1.7. The in vitro cytotoxicity of these polymers was determined and their antitumor activity was evaluated. The IC values (the drug concentration at inhibition of 50% tumor growth) indicated that the synthesized polymers were much better inhibitors of cancer cells and showed lower cytotoxicity than the free 5-FU. The in vivo antitumor activity of the conjugates was examined using mice bearing the sarcoma 180 tumor cell line. The life spans (T/C) of the mice treated with the conjugates were higher than those treated with the free 5-FU. In addition, the synthesized conjugates showed excellent antiangiogenic activity based on an embryo chorioallantoic membrane assay. [ABSTRACT FROM AUTHOR]

Abstract: The interaction of ascorbic acid with 5-methoxy-3,4-dehydroxanthomegnin, an 1,4-naphthoquinone, was investigated using the cytotoxic index for McCoy cells by neutral red assay. The synergstic effect was observed when such compounds were added simultaneously, most probably due to hydrogen peroxide being generated by ascorbate – driven 5-methoxy-3,4-dehydroxanthomegnin redox cycling. Incubation of cells in the presence of 5-methoxy-3,4-dehydroxanthomegnin/ascorbic acid/catalase, an enzyme that destroys H2O2, resulted in an increase of cell survival, reinforcing the involvement of hydrogen peroxide generated as an important oxidizing agent that kills McCoy cells. [Copyright &y& Elsevier]

Abstract: In this paper, a novel pseudo receptor-based QSAR method is proposed as pseudo receptor probes (PRP), including 6 pseudo-probe types defined as empty, electrostatic, steric, hydrophobic, hydrogen bond donor and receptor probes. On that basis, pseudo probe‑ligand interaction is simulated by Gaussian distance-dependent function, predictability of the constructed model is taken as fitness function, and characteristic parameters and arrangements of pseudo probes are optimized by mutational particle swarm optimization (MPSO) algorithm, thereby yielding a “profile” imitating receptor active site. Then by applying PRP, a statistical quantitative structure‑activity relationship (QSAR) model is constructed over 36 newly-discovered selective vascular endothelial growth factor-2 receptor (VEGFR-2) inhibitors of benzoxazole derivatives. Subsequently, the distribution plot of virtual probes is contoured, interpreted from points of statistics and molecular graphics. Thereby, PRP is confirmed of competence to construct robust and predictable pseudo receptor-based QSAR model which possibly provides valuable information on receptor active sites, amenable to definite physicochemical significance. [Copyright &y& Elsevier]

Abstract: Growing attentions have been focused on natural antitumor drugs. Recently, a novel and potent antitumor drug Cheliensisin A (GC-51) with broad-spectrum efficiency has been developed. However, due to its poor water solubility and chemical instability, choosing the appropriate dosage form is of great significance. This study aimed at developing a lyophilized submicron emulsion for GC-51 and further improving the therapeutic index of the drug. The resultant lyophilized GC-51 submicron emulsion was much more stable than its solution, which can be stored for years without significant change on physicochemical properties. And its solubility was increased from 6.74±0.14 to 2.00±0.10mgmL−1. The 50% inhibitory concentration IC50 values were calculated from growth curves by MTT assay on various tumor cell lines. Compared with the IC50 of GC-51 crude drug, that of lyophilized GC-51 submicron emulsion decreased from 24.04±1.97 to 8.23±1.84μgmL−1 on HepG2, and from 31.08±2.56 to 10.85±2.09μgmL−1 on CT-26, from 17.90±1.83 to 7.49±1.87μgmL−1 on HeLa and from 16.38±2.41 to 10.13±2.12μgmL−1 on A549, respectively. In the time-dependent assay of tumor cell viability, lyophilized GC-51 submicron emulsion exhibited significantly lower inhibition rate in the initial action times, but increased gradually afterwards. That means lyophilized submicron emulsion as the vector for GC-51 had some protective and delayed release effect. Further, the in vivo therapeutic efficacy was measured in pulmonary metastasis of colon cancer-bearing BALB/c mice model. An obvious enhanced antitumor activity was observed after administration of lyophilized GC-51 submicron emulsion (P <0.05), which increased from 22.78±3.5 to 41.42±4.2% compared with GC-51 injection. And the life span of tumor-bearing mice in lyophilized GC-51 submicron emulsion group was significantly longer than that of the mice in GC-51 injection and normal saline groups. Compared with crude drug, the lyophilized GC-51 submicron emulsion showed a significantly higher antitumor efficiency both in vivo and in vitro, suggesting a potential application in tumor chemotherapy. [Copyright &y& Elsevier]

Abstract: A series of octahedral Ru(II) polypyridyl complexes, [Ru(phen)2L]2+ (L= R-PIP and PIP=2-phenylimidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized by elementary analysis, 1H NMR and ES-MS, as well as UV–visible spectra and emission spectra. The antitumor activities of these complexes and their corresponding ligands were investigated against mouse leukemia L1210 cells, human oral epidermoid carcinoma KB cells, human promyelocytic leukemia cells (HL-60) and Bel-7402 liver cancer cells by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. It was found that the complexes [Ru(phen)2L]2+ (L= R-PIP) exert rather potent activities against all of these cell lines, especially for the KB cells (IC50 =4.7±1.3μM). The binding affinities of these Ru(II) complexes to CT-DNA (calf thymus DNA), as well as the DNA-unwinding properties on supercoiled pBR322 DNA were also investigated. The results showed that these Ru(II) polypyridyl complexes not only had an excellent DNA-binding property but also possessed a highly effective DNA-photocleavage ability. The structure–activity relationships and antitumor mechanism were also carefully discussed. [Copyright &y& Elsevier]

Abstract: The introduction of an unnatural base pair into DNA enables the expansion of genetic information. To apply unnatural base pairs to in vivo systems, we evaluated the cytostatic toxicity of several nucleoside analogs by an MTT assay. Several nucleoside analogs based on two types of unnatural base pairs were tested. One is a hydrogen-bonded base pair between 2-amino-6-(2-thienyl)purine (s) and pyridin-2-one (y), and the other is a hydrophobic base pair between 7-(2-thienyl)imidazo[4,5-b]pyridine (Ds) and pyrrole-2-carbaldehyde (Pa). Among the nucleoside analogs, the ribonucleoside of 6-(2-thienyl)purine possessed the highest cytostatic activity against CCRF-CEM and especially HT-1080, as well as the normal fibroblast cell line, WI-38. The other analogs, including its 2′-deoxy, 2-amino, and 1-deazapurine nucleoside derivatives, were less active against CCRF-CEM and HT-1080, and the toxicity of these nucleosides toward WI-38 was low. The nucleosides of y and Pa were inactive against CCRF-CEM, HT-1080, and WI-38. In addition, no cytostatic synergism was observed with the combination of the pairing nucleosides of s and y or Ds and Pa. [Copyright &y& Elsevier]

Abstract: Binding effect of the antitumor complex rhodium(II) acetate [Rh2(O2CCH3)4] (Rh1) to the plasmid pUC19 DNA has been studied under different molar ratio of Rh1 compound to base pair of pUC19 DNA (Rf ) and reaction time. The Rh1 binding inhibited the activity of restriction enzyme. The binding effect was monitored using gel electrophoresis. The results indicate that at least one Rh1 binds with the recognition sequence and the binding has no preference between A–T and G–C pairs. At high value of Rf =100, ICP-MS (Inductively Coupled Plasma Mass Spectrometry) measurement confirmed that 46% of Rh1 binds to DNA. PCR amplification of the DNA was also inhibited by the Rh1 binding. The transformation experiment using Escherichia coli suggested that the cell growth was inhibited after binding the Rh1 to the plasmid. These results indicated that DNA synthesis could be inhibited both in vitro and in vivo by the Rh2(O2CCH3)4 binding. [Copyright &y& Elsevier]

Aim: To investigate whether a similar process mediates cytotoxicity of 1- O-octadecyl-2- O-methyl- rac-glycero-3-phosphocholine (ET-18-OCH3, edelfosine) in both yeasts and human tumor cells. Methods: A modified version of a previously described assay for the intracellular conversion of nitro blue tetrazolium to formazan by superoxide anion was used to measure the generation of reactive oxygen species (ROS). Apoptotic yeast cells were detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. DNA fragmentation and the generation of ROS were measured by cytofluorimetric analysis in Jurkat cells. Results: Edelfosine induced apoptosis in Saccharomyces cerevisiae, as assessed by TUNEL assay. Meanwhile, edelfosine induced a time- and concentration-dependent generation of ROS in yeasts. Rotenone, an inhibitor of the mitochondrial electron transport chain, prevented ROS generation and apoptosis in response to edelfosine in S cerevisiae.α-Tocopherol abrogated the edelfosine-induced generation of intracellular ROS and apoptosis. Edelfosine also induced an increase of ROS in human leukemic cells that preceded apoptosis. The overexpression of Bcl-2 by gene transfer abrogated both ROS generation and apoptosis induced by edelfosine in leukemic cells. Changes in the relative mito-chondrial membrane potential were detected in both yeasts and Jurkat cells. Conclusion: These results indicate that edelfosine induces apoptosis in yeasts in addition to human tumor cells, and this apoptotic process involves mitochondria, likely through mitochondrial-derived ROS. These data also suggest that yeasts can be used as a suitable cell model in elucidating the antitumor mechanism of action of edelfosine. [ABSTRACT FROM AUTHOR]

Abstract: The antitumor drug, DE-310, is the slow release form of the camptothecin derivative DX-8951. We investigated a toxicological profile of meningoceles in SD rat fetuses, whose mothers received intravenous DE-310 at several doses, and the time course changes of histology. DE-310 induced a meningocele in the posterior fontanelle of live fetuses by the four-time administration of 0.3mg/(kgday) or more during the organogenetic period, or by a single administration of 1.0mg/kg, particularly, between days 7 and 13 of gestation with an incidence of 100%. The meningocele was caused by the principal ingredient DX-8951. The earliest histological change was focal congestion between the skin and cerebrum, followed by the formation of a space covered by thinned epidermis with necrosed basal cells, hemorrhage in the surrounding connective tissues, cerebrum and ventricles, cavitation of the cerebrum, and incomplete formation of the skull bones and subarachnoid space. DE-310 was characterized as preferentially inducing meningocele (meningoencephalocele in severe cases) in rat fetuses. [Copyright &y& Elsevier]