Cytostatic Activity Research Articles

Silver complexes with heterocyclic thioamide and tertiary arylphosphane ligands: Synthesis, crystal structures, in vitro and in silico antibacterial and cytotoxic activity, and interaction with DNA

Herein we report on the synthesis and molecular structures of six silver(I) mixed-ligand complexes containing a heterocyclic thioamide [4-phenyl-imidazole-2-thione (phimtH) or 2,2,5,5-tetramethyl-imidazolidine-4-thione (tmimdtH)] and a tertiary arylphosphane [triphenylphosphine (PPh3), tri-o-tolylphosphane (totp)] or diphosphane [(1,2-bis(diphenylphosphano)ethane (dppe), bis(2-diphenylphosphano-phenyl)ether (DPEphos) or 4,5-bis(diphenylphosphano)-9,9-dimethylxanthene) (xantphos)]. The interaction of the compounds with calf-thymus DNA (CT DNA), as monitored directly via UV–vis spectroscopy and DNA-viscosity measurements and indirectly via its competition with ethidium bromide for DNA-intercalation sites, is suggested to take place via an intercalative mode. The new complexes show selective significant in vitro antibacterial activity against four bacterial strains. The antiproliferative effects and cytostatic efficacies of the complexes against four human cancer cell lines were evaluated. The best cytostatic and cytotoxic activity was appeared for the complexes bearing the phimtH moiety. In order to explain the described in vitro activity of the complexes, and to approach a possible mechanism of action, molecular docking studies were adopted on the crystal structure of CT DNA, DNA-gyrase, human estrogen receptor alpha and a cell-cycle specific target protein, human cyclin-dependent kinase 6.

Identification of Pathways of A498 Human Kidney Carcinoma Cell Death under the Action of Gratiola officinalis L. Extract and Green Tea Flavonoids Using Fluorescence Imaging Techniques

Using fluorescence methods for visualization of human tumor cell apoptosis and necrosis in vitro, the antitumor effects of flavonoid-containing Gratiola officinalis L. and green tea extracts at ultralow concentrations on A498 human kidney carcinoma cells after 24 and 48 h were compared. Fluorescent dyes (propidium iodide and acridine orange) were used in the “living and dead” test, which made it possible to identify the total number of cells that died by necrosis and apoptosis, as well as cells in which apoptosis has started and apoptotic bodies or pycnosis of the nucleus were detected. Gratiola officinalis L. extract had the most pronounced cytostatic activity 48 h after exposure; the number of cells per field of view decreased by a factor of 1.5 compared with the control. Green tea extract at a concentration of 0.0288 mg/mL had the most pronounced cytotoxic activity; its manifestation was growing 48 h after exposure. Gratiola officinalis L. extract exhibited cytotoxic activity at lower concentrations (0.0036 mg/mL).

Effects of Haloperidol and Cyproheptadine on the Cytoskeleton of the Sea Urchin Embryos

Early sea urchin embryos are sensitive to agonists and antagonists of transmitter receptors, both metabotropic and channel ones. In this work, we studied mechanisms of the cytostatic action of cyproheptadine and haloperidol–antagonists of serotonin 5HT2 receptors and dopamine D2 receptors, respectively. For this purpose, we employed the model of the blockade of the first cleavage division in sea urchin, which allows quantifying the effects of embryotoxic substances. The action of haloperidol and cyproheptadine is mediated by the effects on cytoskeleton elements. Both antagonists caused an increase in the degree of polymerization of the actin cytoskeleton, both in the cortical layer and in the cytoplasm. In addition, both antagonists affected the tubulin cytoskeleton: haloperidol predominantly disturbed spatial organization of the mitotic spindle, while cyproheptadine caused a complete depolymerization of tubulin and arrest of mitotic processes. The results indicate that cytostatic effects of dopamine and serotonin antagonists on cleavage divisions of sea urchin embryos are mediated by similar and/or crosstalk molecular mechanisms but also have significant differences that require further research.

The Real Mechanism of Action of Cyclophosphamide and Other Oxazaphosphorine Cytostatics

The Real Mechanism of Action of Cyclophosphamide and Other Oxazaphosphorine Cytostatics

Potentially Bioaccessible Phenolics from Mung Bean and Adzuki Bean Sprouts Enriched with Probiotic-Antioxidant Properties and Effect on the Motility and Survival of AGS Human Gastric Carcinoma Cells.

Gastric digests from mung (MBS) and adzuki (ABS) bean sprouts enriched with probiotic Lactobacillus plantarum 299v were tested for their antioxidant potential, as well as antiproliferative and antimotility properties, in human stomach cancer cells (AGS). The digest of ABS contained quercetin and kaempferol derivates, while kaempferol and apigenin derivates were dominant in MBS. Compared to the controls, the probiotic-rich sprouts had a higher antioxidant potential—by 13% and 9%, respectively. Adzuki bean sprouts decreased the viability of AGS already at low concentrations (25% motility inhibitions). MBS and ABS displayed dose-independent cytostatic effects. The ABS extracts decreased the proliferation of AGS more effectively than the MBS extracts—0.2‰ ABS exerted c.a. 70% of inhibitions. Moreover, the phytochemicals from the probiotic-rich sprouts considerably reduced this activity. The increased vinculin level, the apoptotic shape of cell nuclei, and the reduced cell motility and proliferation indicate that the extracts exhibited cytostatic and cytotoxic activity.

Selective enrichment of ailanthone from leaves of ailanthus altissima by tandem reverse phase/molecularly imprinted solid phase extraction

The biological activity of extracts from Ailanthus altissima is mainly due to the presence of ailanthone, a compound belonging to the quassinoid class. Recently, attention has been paid to its strong cytostatic activity. However, the extraction of ailanthone is based on very long and demanding procedures, which keep the price of the commercial product very high. Thus, the development of selective adsorbents for the purification of ailanthone from A. altissima leaves extracts could help in reduce the costs of production. In this work, we describe the rational design of a molecularly imprinted polymer selective for ailanthone based on the screening of a 96-members not-imprinted polymeric library to rapidly identify pre-polymerization mixtures able to generate MIPs with enhanced binding properties. A 4-vinylpyridine-co-trimethylolpropane trimethacrylate polymer showed high binding towards ailanthone. It was used to prepare an imprinted polymer with acetonitrile showed interesting binding affinity (Keq = 18.3 × 103 L mol−1), high imprinting factor (IF = 3.8) and fast binding kinetics (kass = 0.390 min−1, kdis = 0.021 mol L−1 min−1). The imprinted polymer was used to develop a successful purification protocol of extracts from Ailanthus altissima leaves. The purification was based on the combination of a preliminary clean-up of Soxhlet extracts onto a reverse phase-C18 cartridge and the subsequent isolation of ailanthone by a molecularly imprinted solid phase extraction. This approach allowed efficiently purifying the ailanthone contained in aqueous or methanolic Soxhlet extracts with high yields compared to the quantities reported in literature (water: 0.756 ± 0.027 mg g−1; methanol: 0.770 ± 0.030 mg g−1). Moreover, it allows processing sample volumes up to 15 mL without significant losses of the target compound.

Leucinostatins from Ophiocordyceps spp. and Purpureocillium spp. Demonstrate Selective Antiproliferative Effects in Cells Representing the Luminal Androgen Receptor Subtype of Triple Negative Breast Cancer.

The structures of four leucinostatin analogues (1-4) from Ophiocordyceps spp. and Purpureocillium spp. were determined together with six known leucinostatins [leucinostatins B (5), A (6), B2 (7), A2 (8), F (9), and D (10)]. The structures of the metabolites were established using a combination of analytical methods including HRESIMS and MS/MS experiments, 1D and 2D NMR spectroscopy, chiral HPLC, and advanced Marfey's analysis of the acid hydrolysate, as well as additional empirical and chemical methods. Compounds 1-10 were evaluated for their biological effects on triple negative breast cancer (TNBC) cells. Leucinostatins 1-10 showed selective cytostatic activities in MDA-MB-453 and SUM185PE cells representing the luminal androgen receptor subtype of TNBC. This selective activity motivated further investigation into the mechanism of action of leucinostatin B (5). The results demonstrate that this peptidic fungal metabolite rapidly inhibits mTORC1 signaling in leucinostatin-sensitive TNBC cell lines, but not in leucinostatin-resistant cells. Leucinostatins have been shown to repress mitochondrial respiration through inhibition of the ATP synthase, and we demonstrated that both the mTORC1 signaling and LAR-selective activities of 5 were recapitulated by oligomycin. Thus, inhibition of the ATP synthase with either leucinostatin B or oligomycin is sufficient to selectively impede mTORC1 signaling and inhibit the growth of LAR-subtype cells.

An electrochemical study of 9-chloroacridine redox behavior and its interaction with double-stranded DNA

The electrochemical behavior of 9-chloroacridine (9Cl-A), a precursor molecule for synthesis of acridine derivatives with cytostatic activity, is a complex, pH-dependent, diffusion-controlled irreversible process. Oxidation of 9Cl-A initiates with the formation of a cation radical monomer, continues via the formation of a dimer subsequent oxidation to new cation radical. Reduction of 9Cl-A produces radical monomers which are stabilized by dimer formation. The investigation was performed using cyclic, differential pulse and square wave voltammetry at a glassy carbon electrode. The interaction between 9Cl-A and double-stranded DNA (dsDNA) was investigated using a multilayer dsDNA-electrochemical biosensor and 9Cl-A solutions from 1.0×10-7M (the lowest 9Cl-A concentration whose interaction with DNA was possible to detect) up to 1×10-4M. These allowed the binding constant, K=3.45×105M-1 and change in Gibbs free energy of the formed adsorbed complex to be calculated. Complex formation was a spontaneous process proceeding via 9Cl-A intercalation into dsDNA inducing structural changes. The intercalation of 9Cl-A into dsDNA was supported by molecular docking analysis.The combination of simple methodology and the use of biosensors to investigate DNA interactions is a powerful tool to offer insight into aspects of drug design during pharmaceutical development.

The Prospect of Creating Medicines Based on Selenium Nanoparticles (Review)

Introduction. The prospects of using nanoparticles in the production of medicines are widely discussed in the literature. In 2018 alone, the quantity of registration certificates issued by national regulators for medicines that use nanoparticles in one form or another is around forty. Most of them are medicines based on liposomes, polymers, iron oxides, micelles. So far, no registration certificates have been issued for selenium nanoparticles. One of the reasons for this situation in this area, from our point of view, is that the mechanisms of interaction of nanoparticles with cells are not sufficiently studied. The lack of basic research in this area is one of the main obstacles to the development of new-generation drugs based on nanoparticles.Text. This review is devoted to the analysis of scientific data on the interaction of selenium nanoparticles with different types of cells. The article discusses the biological properties of selenium and its role in cell metabolism. Data on the cytotoxic effect of selenium nanoparticles on various cell cultures are presented. Methods of preparation of nanoparticles and methods for studying the interaction of nanoparticles with cell cultures are described.Conclusion. Analysis of the literature data allows us to draw conclusions about the relevance of research on the interaction of selenium nanoparticles with living cells. This is necessary to determine the mechanisms of selenium nanoparticles absorption, study their cytotoxic and / or cytostatic action, and distribution in cells. Investigation of the biological interaction of selenium nanoparticles with tumor and normal cells will determine the most informative methods for registering and quantifying their antitumor activity, which is relevant for the development of new drugs to treat cancer.

EndoTAG-1 plus gemcitabine versus gemcitabine alone in patients with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas failed on FOLFIRINOX treatment (NCT03126435).

TPS4669 Background: Pancreatic cancer (PC) is the 3rd deadliest cancer in the United State surpassing breast cancer in 2016, with the overall survival rate of - 9% for those newly diagnosed individuals. The notorious disease is set to become the 2nd leading cause of death from cancer by 2020 in US (National Cancer Institute, NIH). FOLFIRINOX regimen is one of the standard 1st-line treatments for PC patients with good performance status; however, there is currently no standard of care in 2nd-line therapy after FOLFIRINOX failure. EndoTAG-1 is a novel formulation of cationic liposomes embedded with Paclitaxel, which specifically displays antivascular and antiangiogenic activities. By binding and internalizing at tumor endothelial cells after intravenous administration, the cytostatic activity of paclitaxel will be targeted to the activated tumor endothelial cells. Methods: Eligible patients with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas failed on FILFIRINOX treatment will be screened and randomized (1:1) into one of the two arms in the study (n=218). The primary endpoint of the study is overall survival (OS), with secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and quality of life (QoL). Arm A: EndoTAG-1 plus Gemcitabine: Patients will receive intravenous injection with EndoTAG-1 (22 mg/m2) twice weekly plus gemcitabine (1,000 mg/m2) once weekly for consecutively 3 weeks followed by 1 week rest. The treatment will be repeated every 4 weeks, with 8 weeks per cycle. The treatment will be kept until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. Arm B: Gemcitabine: Patients will receive gemcitabine (1,000 mg/m2) once weekly for consecutive 3 weeks followed by 1 week rest. The treatment will be repeated every 4 weeks, with 8 weeks per cycle. The treatment will be kept until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. The phase III trial began enrollment since November 2018. The trial will continue as planned from the last review in January 2020. Clinical trial information: NCT03126435 .

Piceatannol-Loaded Emulsomes Exhibit Enhanced Cytostatic and Apoptotic Activities in Colon Cancer Cells.

Piceatannol (PIC), a naturally occurring polyphenolic stilbene, has pleiotropic pharmacological activities. It has reported cytotoxic activities against different cancer cells. In the present study, PIC emulsomes (PIC-E) were formulated and assessed for cytotoxic activity. A Box–Behnken design was employed to investigate the influence of formulation factors on particle size and drug entrapment. After optimization, the formulation had a spherical shape with a particle size of 125.45 ± 1.62 nm and entrapment efficiency of 93.14% ± 2.15%. Assessment of cytotoxic activities indicated that the optimized PIC-E formula exhibited significantly lower IC50 against HCT 116 cells. Analysis of the cell cycle revealed the accumulation of cells in the G2-M phase as well as increased cell fraction in the sub-G1 phase, an indication of apoptotic-enhancing activity. Staining of cells with Annexin V indicated increased early and late apoptosis. Further, the cellular contents of caspase - 3 and Bax/Bcl-2 mRNA expression were significantly elevated by PIC-E. In addition, the mitochondrial membrane potential (MMP) was disturbed and reactive oxygen species (ROS) production was increased. In conclusion, PIC-E exhibited superior cell death-inducing activities against HCT 116 cells as compared to pure PIC. This is mediated, at least partly, by enhanced pro-apoptotic activity, disruption of MMP, and stimulation of ROS generation.

Promotion of liver regeneration and anti‑fibrotic effects of theTGF‑β receptor kinase inhibitor galunisertib in CCl4‑treated mice.

The cytokine transforming growth factor‑β (TGF‑β) serves a key role in hepatic fibrosis and has cytostatic effects on hepatocytes. The present study investigated the anti‑fibrogenic and regenerative effects of the TGF‑β receptor typeI kinase inhibitor galunisertib (LY2157299) in mice with carbon tetrachloride (CCl4)‑induced liver cirrhosis and invitro. Mice were intraperitoneally treated with CCl4 for 8weeks. At week5, the mice were divided randomly into four treatment groups: Vehicle‑treated; and treated with low‑; middle‑; and high‑dose galunisertib, which was administered from weeks5‑8. The mice were sacrificed after 8weeks of CCl4treatment. Liver fibrosis, as evaluated by histology and determination of hydroxyproline content, progressed during week4‑8 of CCl4 treatment in the vehicle‑treated mice. Galunisertib treatment dose‑dependently prevented liver fibrosis, as demonstrated by the direct inhibition of α‑smooth muscle actin‑positive activated hepatic stellate cells (HSCs) after 8weeks of CCl4treatment. The levels of active matrix metalloproteinase (MMP)‑9 in galunisertib‑treated livers were significantly increased compared with the vehicle‑treated livers. In the high‑dose group, the number of PCNA‑positive hepatocytes and endothelial cells markedly increased compared with the vehicle group. Reverse transcription‑quantitative PCRanalysis verified that interleukin‑6 and epiregulin expression levels were significantly increased in livers from the group treated with high‑dose galunisertib compared with the vehicle‑treated group. Galunisertib inhibited the proliferation of activated HSCs and collagen synthesis in addition to restoring MMPactivity. Moreover, galunisertib promoted liver remodeling by proliferating hepatocytes and vascular endothelial cells, while significantly increasing liver weight. These results are consistent with the cytostatic action of TGF‑β that negatively regulates liver regeneration, and demonstrated that galunisertib inhibited TGF‑βsignaling, halted liver fibrosis progression and promoted hepatic regeneration. The results of the present study suggest that galunisertib may be an effective treatment for liver cirrhosis.

Synthesis and Cytostatic Activity of New Mepregenol 17-Acetate Derivatives with Respect to Hela Cancer Cell Culture

New mepregenol 17-acetate derivatives with potential cytotoxicity were synthesized. Mepregenol 17-acetate 3-acrylate (III) was shown to exhibit potent cytotoxicity although the ester of N-benzylpyrrolidine-3-carboxylic acid (IV) had weaker activity that was comparable with those of megestrol acetate and progesterone. The IC50 values for III, IV, progesterone, and megestrol acetate were 30, 200, 480, and 130 μMwith respect to native HeLa culture and 9.1, 180, 5.6, and 115 μm for an estradiol-stimulated culture of HeLa, respectively. The cytotoxicities of steroids III and IV correlated with their DNA-damaging effect in a DNA comet assay. Thus, III was promising for further research as an antitumor compound with respect to estradiol-dependent tumors.

Design, Synthesis, and Biological Evaluation of Novel C5-Modified Pyrimidine Ribofuranonucleosides as Potential Antitumor or/and Antiviral Agents.

Nucleoside analogues are well-known antitumor, antiviral, and chemotherapeutic agents. Alterations on both their sugar and the heterocyclic parts may lead to significant changes in the spectrum of their biological activity and the degree of selective toxicity, as well as in their physicochemical properties. C5-arylalkynyl-β-D-ribofuranonucleosides 3-6, 3΄-deoxy 12-15, 3΄-deoxy-3΄-C-methyl- β-D-ribofurananucleosides 18-21 and 2΄-deoxy-β-D-ribofuranonucleosides 23-26 of uracil, were synthesized using a one-step Sonogashira reaction under microwave irradiation and subsequent deprotection. All newly synthesized nucleosides were tested for their antitumor or antiviral activity. Moderate cytostatic activity against cervix carcinoma (HeLa), murine leukemia (L1210) and human lymphocyte (CEM) tumor cell lines was displayed by the protected 3΄-deoxy derivatives 12b,12c,12d, and the 3΄-deoxy-3΄-methyl 18a,18b,18c. The antiviral evaluation revealed appreciable activity against Coxsackie virus B4, Respiratory syncytial virus, Yellow Fever Virus and Human Coronavirus (229E) for the 3΄-deoxy compounds 12b,14, and the 3΄-deoxy-3΄-methyl 18a,18c,18d, accompanied by low cytotoxicity. This report describes the total and facile synthesis of modified furanononucleosides of uracil, with alterations on both the sugar and the heterocyclic portions. Compounds 12b,14 and 18a,c,d showed noticeable antiviral activity against a series of RNA viruses and merit further biological and structural optimization investigations.

Isoliquiritigenin Nanosuspension Enhances Cytostatic Effects in A549 Lung Cancer Cells.

Isoliquiritigenin, a flavonoid extracted from licorice root, has been shown to be active against most cancer cells; however, its antitumor activity is limited by its poor water solubility. The aim of this study was to develop a stable isoliquiritigenin nanosuspension for enhanced solubility and to evaluate its in vitro cytostatic activity in A549 cells. The nanosuspension of isoliquiritigenin was prepared through wet media milling with HPC SSL (hydroxypropyl cellulose-SSL) and PVP K30 (polyinylpyrrolidone-K30) as stabilizers, and the samples were then characterized according to particle size, zeta-potential, SEM (scanning electron microscopy), TEM (transmission electron microscopy), DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction), FTIR (Fourier transform infrared spectroscopy), XPS (X-ray photoelectron spectroscopy), and in vitro release. The isoliquiritigenin nanosuspension prepared with HPC SSL and PVP K30 had particle sizes of 238.1 ± 4.9 nm and 354.1 ± 9.1 nm, respectively. Both nanosuspensions showed a surface charge of approximately - 20 mV and a lamelliform or ellipse shape. The dissolution of isoliquiritigenin from the 2 nanosuspensions was markedly higher than that of free isoliquiritigenin. In vitro studies on A549 cells indicated that the cytotoxicity and cellular uptake significantly improved after treatment with both nanosuspensions in comparison to the isoliquiritigenin solution. Furthermore, cell apoptosis analysis showed a 7.5 - 10-fold increase in the apoptosis rate induced by both nanosuspensions compared with pure drug. However, the cytotoxicity of pure drug and nanosuspension on normal cells (HELF) was lower, which indicated both isoliquiritigenin nanosuspensions have low toxicity to normal cells. Therefore, the isoliquiritigenin nanosuspension prepared with HPC SSL and PVP K30 as stabilizers may be a promising approach to improve the solubility and cytostatic activity of isoliquiritigenin.

Metformin in Oncology - How Far Is Its Repurposing as an Anticancer Drug?

Metformin is the most commonly used antidiabetic drug with a plethora of proven metabolic and cardiovascular beneficial effects and exceptional safety profile. On top of the established metabolic effects, retrospective epidemiologic evidence shows that metformin use is associated with decreased cancer risk and/or improved disease prognosis in diabetic cancer patients on metformin compared to those treated with different antidiabetic drugs. This is a sound argument for eventual repurposing metformin as an adjuvant drug in oncology; however, evidence-based data are currently needed to establish this. Metformin is a biguanide that in the context of type 2 diabetes primarily targets the liver. Metformin inhibits oxidative phosphorylation which leads to the suppression of gluconeogenesis and causes decrease of blood glucose concentration. Mechanisms responsible for metformin anti-neoplastic effect have been investigated extensively, and key events seem to centralize around its ability to induce intracellular energetic stress with subsequent changes of metabolism resulting in cytostatic or cytotoxic action. Large clinical experience with metformin in the treatment of diabetes together with its plausible effects on different cancer cell types initiated a number of clinical trials that tested the hypothesis that metformin might have a beneficial effect in the treatment of cancer. The aim of this review is to compile recent advances in our understanding of metformin antineoplastic effects and to give a summary of the results of recent clinical trials of metformin for treatment of different cancer types.

A Nuclear Magnetic Insight Towards the Cytostatic Potential of Medicinal Plant Extracts Replay to Al Wihibi et al Biomedica 2019;35(4):203-209

<p>Cytostatic activities of water and organic extracts prepared from medicinal higher plants including Ducrosia anethifolia should be analyzed by taking into account the “hidden” magnetic isotope effects of stable metal isotopes (25Mg, 43Ca, 67Zn …) pre-(bio) fractionated in the plant tissues. A multi-collector inductively coupled plasma mass spectrometry (MC – ICPMS) might be successfully employed to reveal and detail this specific peculiarity for further pharmacological applications.</p>

In Vitro Anti-Prostate Cancer Activity of Two Ebselen Analogues.

Scientific research has been underway for decades in order to develop an effective anticancer drug, and it has become crucial to find a novel and effective chemotherapeutics in the case of prostate cancer treatment. Ebselen derivatives have been shown to possess a variety of biological activities, including cytostatic and cytotoxic action against tumor cells. In this study, the cytotoxic effect and anticancer mechanism of action of two organoselenium compounds— (N-allyl-1,2-benzisoselenazol-3(2H)-one (N-allyl-BS) and N-(3-methylbutyl)-1,2-benzisoselenazol-3(2H)-one) (N-(3-mb)-BS)—were investigated on two phenotypically different prostate cancer cell lines DU 145 and PC-3. The influence of analyzed compounds on the viability parameter was also assessed on normal prostate cell line PNT1A. The results showed that both organoselenium compounds (OSCs) efficiently inhibited cancer cell proliferation, whereas normal PNT1A cells were less sensitive to the analazyed ebselen analouges. Both OSCs induced G2/M cell cycle arrest and prompted cell death through apoptosis. The detection of cleaved Poly (ADP-ribose) Polymerase (PARP) confirmed this. In addition, N-allyl-BS and N-(3-m)-b-BS increased the level of reactive oxygen species (ROS) formation, however only N-allyl-BS induced DNA damage. Based on our data, we assume that OSCs’ anticancer action can be associated with oxidative stress induction and inactivation of the Akt- dependent signalling pathway. In conclusion, our data demonstrate that ebselen derivatives showed strong cytotoxic efficiency towards prostate cancer cells and may be elucidated as a novel, potent anticancer agent.

Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells

Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitors are increasingly studied for their potential cytotoxic properties. Moreover, the incorporation of carboranes in structures of established anti-inflammatory drugs can improve the potency and metabolic stability of the inhibitors. Herein, we report the synthesis of carborane-containing derivatives of rofecoxib that display remarkable cytotoxic or cytostatic activity in the micromolar range with excellent selectivity for melanoma and colon cancer cell lines over normal cells. Furthermore, it was shown that the carborane-modified derivatives of rofecoxib showed different modes of action that were dependent on the cell type.

A Tumor-in-Host DEB-Based Approach for Modeling Cachexia and Bevacizumab Resistance.

Adequate energy intake and homeostasis are fundamental for the appropriate growth and maintenance of an organism; the presence of a tumor can break this equilibrium. Tumor energy requests can lead to extreme weight loss in animals and cachexia in cancer patients. Angiogenesis inhibitors, acting on tumor vascularization, counteract this tumor-host energy imbalance, with significant results in preclinical models and more limited results in the clinic. Current pharmacokinetic-pharmacodynamic models mainly focus on the antiangiogenic effects on tumor growth but do not provide information about host conditions. A model that can predict energetic conditions that provide significant tumor growth inhibition with acceptable host body weight reduction is therefore needed. We developed a new tumor-in-host dynamic energy budget (DEB)-based model to account for the cytostatic activity of antiangiogenic treatments. Drug effect was implemented as an inhibition of the energy fraction subtracted from the host by the tumor. The model was tested on seven xenograft experiments involving bevacizumab and three different tumor cell lines. The model successfully predicted tumor and host body growth data, providing a quantitative measurement of drug potency and tumor-related cachexia. The inclusion of a hypoxia-triggered resistance mechanism enabled investigation of the decreased efficacy frequently observed with prolonged bevacizumab treatments. In conclusion, the tumor-in-host DEB-based approach has been extended to account for the effect of bevacizumab. The resistance model predicts the response to different administration protocols and, for the first time, the impact of tumor-related cachexia in different cell lines. Finally, the physiologic base of the model strongly suggests its use in translational human research. SIGNIFICANCE: A mathematical model describes tumor growth in animal models, taking into consideration the energy balance involving both the growth of tumor and the physiologic functions of the host.