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PubMed2006

Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer.

BACKGROUND: Linomide, Figure 1, produces robust and consistent in vivo growth inhibition of prostate cancer models via its anti-angiogenic activity and inhibition of autoimmune encephalomyelitis models of multiple sclerosis (MS). MS clinical trials were discontinued because of unacceptable toxicity, due to dose-dependent induction of proinflammation. METHODS: Therefore, linomide analogs were initially screened to determine their in vivo potency to inhibit growth of the Dunning R-3327 AT-1 rat prostate cancer model in rats and their potency to inhibit angiogenesis in a Matrigel assay in mice. RESULTS: Based upon its superior potency (i.e., 30- to 60-fold more potent than linomide) in these assays and its lack of a proinflammation in the Beagle-dog, ABR-215050 (tasquinimod), Figure 1, was characterized for dose-response ability to inhibit the growth of a series of four additional human and rodent prostate cancer models in mice. Pharmacokinetic analysis following oral dosing documented that blood and tumor tissue levels of ABR-215050 as low as 0.5-1 microM are therapeutically effective. This efficacy is correlated with inhibition of angiogenesis in a variety of assays (endothelial capillary tube formation, aortic ring assay, chorioallantoic membrane assay, real-time tumor blood flow and PO(2) measurements, tumor blood vessel density, and tumor hypoxic and apoptotic fractions). CONCLUSIONS: Based upon its robust and consistent anti-angiogenic activity and thus tumor growth, ABR-215050 has entered clinical trials for the treatment of prostate cancer.

Angiogenesis Inhibitors↗
PubMed2006

An orthotopic colon cancer model for studying the B7-H3 antitumor effect in vivo.

We established an orthotopic animal model of colon cancer in mice and applied this model to study the antitumor effects of B7-H3, the newest member of the B7 family of costimulatory molecules. Colon-26 murine colon adenocarcinoma cells were inoculated into the cecal subserosum of mice to induce colon tumor growth. The tumor growth rate and the survival time of the mice were observed. A stable B7-H3 transfected Colon-26 cell line was established and the immunogenic effect was investigated. All mice implanted with wild-type tumor cells had tumor growth in the colon and died. The mean survival rate was 23 days. Mice implanted with C26-B7-H3 had a significantly prolonged survival time of 38 days. Our data suggest that B7-H3 exerts an antitumor effect on adenocarcinoma of the colon and may be considered as an adjuvant immunotherapy in the treatment of colon cancers. Our orthotopic animal model of colon cancer in mice could be applied to in vivo experimental studies of colon cancer.

Adenocarcinoma↗
PubMed2006

Targeting c-Src kinase enhances tamoxifen's inhibitory effect on cell growth by modulating expression of cell cycle and survival proteins.

PURPOSE: Many studies have implicated the non-receptor tyrosine kinase c-Src in the development and metastatic progression of many types of cancer. In breast cancer, c-Src has been proposed to mediate the actions of estrogen in cell cycle progression. METHODS: In this study we investigated the interaction between c-Src inhibition and estrogen receptor (ER) function using the ER-positive and tamoxifen-sensitive MCF-7 breast cancer cells. RESULTS: Pharmacological inhibition of c-Src blocked estrogen-dependent proliferation in MCF-7 cells and enhanced the inhibitory effects of tamoxifen or estrogen-deprivation on cell growth. Maximum inhibition (95%) of cell growth was obtained when tamoxifen and c-Src blockade were combined. Inhibition of c-Src kinase decreased levels of the ER targets c-Myc and cyclin D1 expression but not of Bcl-2. Nevertheless, blocking c-Src kinase in tamoxifen-treated MCF-7 cells led to apoptosis. Inhibition of c-Src kinase altered the ratio of Mcl-1 isoforms in favor of cell death whereas expression of the proapoptotic molecules Bad, Bak, and Bax was not altered. Surprisingly, blocking ER function increased the levels of Bad phosphorylation at serine 112 (BadpS112), an inactive (nonapoptotic) form of Bad. This inactivation of Bad upon ER blockade seemed to depend on c-Src function as chemical inhibition of c-Src kinase reduced BadpS112 levels in cells with impaired ER function but not in estrogen-treated cells. CONCLUSION: These results indicate a crucial role for c-Src kinase in the survival of ER-positive breast cancer cells only when ER function is blocked. Therefore, this study suggests that targeting simultaneously c-Src and ER may effectively inhibit growth of ER-positive breast cancer.

Apoptosis↗
PubMed2006

Down-regulation of an inhibitor of cell growth, transmembrane protein 34 (TMEM34), in anaplastic thyroid cancer.

PURPOSE: Ansaplastic thyroid cancer (ATC) is one of the most lethal malignancies, but the carcinogenic mechanism of ATC has not been clarified. Recently, we performed a cDNA microarray analysis and identified transmembrane protein 34 (TMEM34) that down-regulated in anaplastic thyroid cancer cell lines (ACL)s as compared to normal thyroid tissues. METHODS: To investigate the role of TMEM34 in ATC carcinogenesis, we examined expression levels of TMEM34 in ACLs as well as differentiated thyroid cancers (DTC)s and normal human tissues. To explore the effect of TMEM34 in ATC development, cell-growth assays with KTA2 cells were performed. RESULTS: Expression of TMEM34 was down-regulated in all 11 ACLs, as compared to either normal thyroid tissues or cell lines derived from papillary or follicular thyroid cancers. TMEM34 was expressed ubiquitously in normal human tissues tested. Transfection of TMEM34 into KTA2 cells led to inhibition of cell growth. CONCLUSIONS: Our findings suggest that TMEM34 might be a tumor suppressor gene, associated with the development of ATC from DTC.

Carcinoma↗
PubMed2005

Cell wall pectins and xyloglucans are internalized into dividing root cells and accumulate within cell plates during cytokinesis.

Recently, we have reported that cell wall pectins are internalized into apical meristem root cells. In cells exposed to the fungal metabolite brefeldin A, all secretory pathways were inhibited, while endocytic pathways remained intact, resulting in accumulation of internalized cell wall pectins within brefeldin A-induced compartments. Here we report that, in addition to the already published cell wall epitopes, rhamnogalacturonan I and xyloglucans also undergo large-scale internalization into dividing root cells. Interestingly, multilamellar endosomes were identified as compartments internalizing arabinan cell wall pectins reactive to the 6D7 antibody, while large vacuole-like endosomes internalized homogalacturonans reactive to the 2F4 antibody. As all endosomes belong topographically to the exocellular space, cell wall pectins deposited in these "cell wall islands", enclosed by the plasma-membrane-derived membrane, are ideally suited to act as temporary stores for rapid formation of cell wall and generation of new plasma membrane. In accordance with this notion, we report that all cell wall pectins and xyloglucans that internalize into endosomes are highly enriched within cytokinetic cell plates and accumulate within brefeldin A compartments. On the other hand, only small amounts of the pectins reactive to the JIM7 antibody, which are produced in the Golgi apparatus, localize to cell plates and they do not accumulate within brefeldin A compartments. In conclusion, meristematic root cells have developed pathways for internalization and recycling of cell wall molecules which are relevant for plant-specific cytokinesis.

Antibodies, Monoclonal↗
PubMed2006

Probing the adaptive response of Escherichia coli to extracellular Zn(II).

The adaptive response of Escherichia coli cells to differing intracellular and extracellular Zn(II) concentrations was evaluated by two-dimensional gel electrophoresis and peptide identifications. Twenty-one Zn(II)-responsive proteins, which were previously not known to be associated with Zn(II), were identified. Most of the proteins were related to cellular metabolism and include membrane transporters and glycolytic and TCA-associated enzymes. The expression levels of no known Zn(II) transporters were identified with these studies. The results of these studies suggest a role of Zn(II) in the expression levels of several E. coli proteins, and the results are discussed in light of recent genomic profiling studies on the adaptive response of E. coli cells to stress by Zn(II) excess.

Cell Growth Processes↗
PubMed1984

A simple method to determine whole cell uptake of radiolabelled oestrogen and progesterone and their subcellular localization in breast cancer cell lines in monolayer culture.

Specific uptake of tritiated 17 beta-oestradiol and R5020, a synthetic progestin, in breast cancer cell lines ( MCF7 and T47D) growing in monolayer culture in multiwell plates has been shown. Binding characteristics, calculated by Scatchard analysis, indicate the presence of steroid receptors of similar affinities and capacities to those already obtained with broken cell preparations. Lysis of the cells by treatment with a hypotonic buffer reveals the subcellular localization of the receptors so the method can be used to study receptor dynamics such as nuclear translocation and processing. Cell growth can be measured by DNA determination directly in the multiwell plates. Thus, the method provides a convenient way of studying the effects of steroid hormones (or any antihormone or chemotherapeutic agent) on growth and receptor content of breast cancer cells in monolayer culture.

Breast Neoplasms↗
PubMed2006

Celecoxib inhibits cellular growth, decreases Ki-67 expression and modifies apoptosis in ovarian cancer cell lines.

BACKGROUND: There is controversy on the safety of inhibitors of cyclooxygenase administered at high doses; however, these drugs have been reported to be effective in the prevention of a variety of human cancers. To determine if celecoxib influences cellular growth, we evaluated several effects in ovarian carcinoma cell lines. METHODS: CAOV3, OVCAR3 and SKOV3 cell lines were exposed to different concentrations of celecoxib (0-100 microM) for 24-96 h. Cellular growth was assessed using a cell viability assay. Immunohistochemistry was performed to evaluate Ki-67 and cleaved caspase-3. Apoptosis was determined by a TUNEL assay, and Western blot was used to determine COX-2 protein expression. RESULTS: We observed a significant decrease in the cellular growth of all cell lines studied exposed to > or = 70 microM of celecoxib for 72 and 96 h (p < 0.02). All cells demonstrated pancytotoxicity at 100 microM of celecoxib. A significant decrease in Ki-67 expression in all cell lines exposed to > or = 30 microM of celecoxib (p < or = 0.05) for 72 h was observed. We observed significant changes in apoptosis and cleaved caspase-3 expression in SKOV3 cells exposed to 50 microM of celecoxib. Downregulation of COX-2 protein expression caused by celecoxib was observed in SKOV3 cells. CONCLUSIONS: We found that celecoxib inhibits cellular growth and proliferation in a dose-dependent manner in all cell lines studied. SKOV3 cells showed an increase in cleaved caspase-3 expression. Additional studies are in progress to evaluate the effects of celecoxib on other aspects of the control of the cell cycle in cancer cells.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Serial analysis of gene expression in sinusoidal endothelial cells from normal and injured mouse liver.

Here we describe gene expression profiles of mouse liver sinusoidal endothelial cells (LSECs) revealed by serial analysis of gene expression (SAGE). We prepared SAGE libraries of LSECs from normal and injured liver by CCl(4) administration, and we obtained 32,867 tags from normal and 37,493 tags from injured liver, representing 6011 unique transcripts. CCl(4) administration upregulated several genes related to cell growth and differentiation (Cdkn1a, Irf1, Il4ra, etc.), whereas it downregulated genes related to cell growth or protein transport (Kdr, Igfbp4, Ap1b1, etc.). To identify genes preferentially expressed in LSEC, we compared our SAGE libraries with 77 publicly available libraries generated from various mouse tissues and cell lines. We identified 23 genes, including Stab2 and uncharacterized genes, as possible markers for LSEC, which will be useful to analyze the specific role for LSECs in normal as well as regenerating liver.

Animals↗
PubMedDate not supplied

Selection with a regulated cell growth switch increases the likelihood of expression for a linked gamma-globin gene.

Several lines of evidence indicate that in vivo drug selection can be used to overcome the low rates of gene transfer and engraftment encountered in many hematopoietic stem cell gene therapy settings. However, whether selection imposed on one transcription cassette effects the likelihood of expression from a second, independent transcription cassette within the same vector has been less well studied. In order to address this issue, we engineered an oncoretrovirus vector to express two separate transcription units: (i) a bicistronic cassette encoding both GFP and a pharmacologically regulated cell growth switch based on the thrombopoietin receptor Mpl; and (ii) a highly position-dependent second cassette encoding human gamma-globin. Studies in cell cultures and in mice transplanted with transduced marrow indicated that selective expansion increased by more than 9-fold the fraction of erythroid cells expressing the linked but separate expression cassette for gamma-globin. This increase was far greater then that observed for the bicistronic GFP gene, and cannot be explained by a simple increase in the fraction of cells containing provirus. These results suggest that selective expansion favors erythroid stem/progenitor cells with provirus integrated at chromosomal sites which are relatively resistant to silencing position effects.

Animals↗
PubMed2004

A history of the study of solid tumour growth: the contribution of mathematical modelling.

A miscellany of new strategies, experimental techniques and theoretical approaches are emerging in the ongoing battle against cancer. Nevertheless, as new, ground-breaking discoveries relating to many and diverse areas of cancer research are made, scientists often have recourse to mathematical modelling in order to elucidate and interpret these experimental findings. Indeed, experimentalists and clinicians alike are becoming increasingly aware of the possibilities afforded by mathematical modelling, recognising that current medical techniques and experimental approaches are often unable to distinguish between various possible mechanisms underlying important aspects of tumour development. This short treatise presents a concise history of the study of solid tumour growth, illustrating the development of mathematical approaches from the early decades of the twentieth century to the present time. Most importantly these mathematical investigations are interwoven with the associated experimental work, showing the crucial relationship between experimental and theoretical approaches, which together have moulded our understanding of tumour growth and contributed to current anti-cancer treatments. Thus, a selection of mathematical publications, including the influential theoretical studies by Burton, Greenspan, Liotta et al., McElwain and co-workers, Adam and Maggelakis, and Byrne and co-workers are juxtaposed with the seminal experimental findings of Gray et al. on oxygenation and radio-sensitivity, Folkman on angiogenesis, Dorie et al. on cell migration and a wide variety of other crucial discoveries. In this way the development of this field of research through the interactions of these different approaches is illuminated, demonstrating the origins of our current understanding of the disease.

Cell Growth Processes↗
PubMed2005

Antiandrogen-like actions of an antioxidant on survivin, Bcl-2 and PSA in human prostate cancer cells.

BACKGROUND: Androgens, while essential for prostate gland development, have been postulated to contribute to carcinogenesis, and antioxidants have been postulated to suppress prostate cancer development. We theorized that antioxidants might suppress prostate cancer cell growth by blocking androgen effects on cell survival. This hypothesis was tested by in vitro studies conducted in ALVA-101, an androgen responsive human prostate cancer cell line. METHODS: ALVA-101 was cultured with or without testosterone (T, 10(-12) M) and pyrrolidinedithiocarbamate (PDTC, 10 microg/mL). Cell Titer 96 AQ, electrophoretic mobility shift assay (EMSA), reverse transcription-polymerase chain reaction (RT-PCR), Northern and Western blot were used to quantify the cell growth, nuclear factor-kappa B (NF-kappaB) activity, mRNAs of survivin, Bcl-2, androgen receptor (AR) and prostate specific antigen (PSA), and proteins of AR and survivin. RESULTS: PDTC suppressed EMSA of NF-kappaB and significantly decreased (p < 0.05) T's stimulatory effects on cell growth, mRNAs of survivin, Bcl-2, AR and PSA and synthesis of proteins of AR and survivin. Antisense to both survivin and Bcl-2 suppressed cell growth. CONCLUSIONS: PDTC, a potent inducer of apoptosis, exerts antiandrogen-like action by reducing AR protein and reversing the stimulatory effects of androgen on potent inhibitors of apoptosis.

Androgen Antagonists↗
PubMed2005

Toward a molecular interpretation of the surface stress theory for yeast morphogenesis.

The surface stress theory was proposed more than twenty years ago to explain morphogenesis of walled organisms. This theory makes simple assumptions on the force that drives microbial growth and how a cell's response to this force generates shape. This classic formulation may now be explained in more detailed molecular terms due to recent advances in the study of yeast morphogenesis with respect to the mechanism of cell polarization, the fine tuning of polarized growth to allocate necessary components to proper locations, and the local and global responses to turgor that provide control over the location and duration of growth.

Actins↗
PubMed2004

Expression of organic cation transporter OCTN1 in hematopoietic cells during erythroid differentiation.

OBJECTIVE: Organic cation/carnitine transporter, OCTN1 (SLC22A4) shows a relatively broad tissue distribution and transports organic cations in a pH-dependent manner. However, its physiological role remains to be clarified. To understand the physiological role of OCTN1, tissue expression of OCTN1 in human and mice was characterized. METHODS: Expression of OCTN1 in various tissues and blood cells was examined by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and flow cytometry analysis. RESULTS: Mouse OCTN1 mRNA was detected in kidney, smooth muscle, and hematopoietic tissues, such as spleen and bone marrow, by RT-PCR analysis. Further study focused on expression of OCTN1 in various types of blood cells. OCTN1 mRNA was detected in myeloid cells in mouse bone marrow, but not in lymphoid cells. Bone marrow nuclear cells positive for TER119, an erythrocyte marker, showed strong expression of OCTN1. Similarly, OCTN1 was strongly expressed in glycophorin A-positive erythroid cells obtained from human cord blood. In Western blot analysis, OCTN1 protein was detected in isolated mouse mature peripheral erythrocytes. Further analysis by RT-PCR and flow cytometry showed OCTN1 was expressed in both glycophorin A-positive and negative erythroid cells after cultivation. These findings suggested that OCTN1 transports compound(s) that are required for erythroid differentiation, maturation, and/or growth. CONCLUSION: The present study demonstrated that OCTN1 is associated with myeloid cells rather than lymphoid cells, and especially with erythroid-lineage cells at the transition stage from immature erythroid cells to peripheral mature erythrocytes.

Animals↗
PubMed2006

Apoptosis-inducing active components from Corbicula fluminea through activation of caspase-2 and production of reactive oxygen species in human leukemia HL-60 cells.

The anti-cancer effects and possible mechanisms of the freshwater clam (Corbicula fluminea Muller) and its active compounds (FME) on cell viability in human leukemia HL-60 cells were investigated. This study demonstrated that FME was able to inhibit cell proliferation in a concentration- and time-dependent manner. Treatment with FME caused induction of caspase-2, caspase-3, caspase-6, caspase-8, and caspase-9 activity in a time-dependent manner, but not affect caspase-1 activity; it induced the proteolysis of DNA fragmentation factor (DFF-45) and poly(ADP-ribose) polymerase (PARP). Induction of cell death by FME was completely prevented by a pan-caspase inhibitor, Z-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) and a caspase-2 inhibitor, Z-Val-Asp-Val-Ala-Asp-FMK (Z-VDVAD-FMK). Furthermore, treatment with FME caused a rapid loss of mitochondrial transmembrane potential, stimulation of generation of reactive oxygen species (ROS), release of mitochondrial cytochrome c into cytosol, and GSH depletion. Anti-oxidants such as N-acetylcysteine, catalase, superoxide dismutase, allopurinol, and pyrrolidine dithiocarbamate, but not diphenylene iodonium, significantly inhibited FME-induced cell death. In addition, the results showed that FME-induced apoptosis was accompanied by up-regulation of Bax and Bad, and down-regulation of Bcl-2 and Bcl-XL. Taken together, induction of apoptosis on HL-60 cells by FME was mainly associated with ROS production, GSH depletion, mitochondrial dysfunction, and caspase activation.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Prooxidant activity and toxicity of nordihydroguaiaretic acid in clone-9 rat hepatocyte cultures.

Nordihydroguaiaretic acid (NDGA) is a polyphenol. It is present at high concentrations in the leaves of the evergreen desert shrub, Larrea tridentate (Creosote bush), which has a long history of medicinal use traditionally by the native Americans and Mexicans. It is generally believed that the antioxidant properties of NDGA are responsible for the medicinal value of this desert shrub. The clone-9 rat hepatocyte cultures were used as an in vitro model to assess the hepatotoxic potential of NDGA and to determine whether it exhibits any prooxidant activity. The hepatocyte cultures were treated with NDGA for 2 h at 37 degrees C at concentrations of 0-100 microM. After the treatment period the cells, the culture supernatants and cell lysates were assayed for evaluation of prooxidant activity and toxicity of NDGA. Oxidative stress level and oxidative cell injury as measured by the peroxidation of membrane lipids and DNA double-strand breaks were used to index prooxidant activity. Cytotoxicity as measured by the leakage of the liver enzyme lactate dehydrogenase (LDH) into the culture medium, mitochondrial function and extent of cell proliferation were used as the endpoints of toxicity. Significant concentration-dependent differences were observed in these biomarkers over the concentration range examined demonstrating the prooxidant activity and toxicity of NDGA in clone-9 rat hepatocyte cultures.

Animals↗
PubMed2006

A mathematical model to study the effects of drugs administration on tumor growth dynamics.

A mathematical model for describing the cancer growth dynamics in response to anticancer agents administration in xenograft models is discussed. The model consists of a system of ordinary differential equations involving five parameters (three for describing the untreated growth and two for describing the drug action). Tumor growth in untreated animals is modelled by an exponential growth followed by a linear growth. In treated animals, tumor growth rate is decreased by an additional factor proportional to both drug concentration and proliferating cells. The mathematical analysis conducted in this paper highlights several interesting properties of this tumor growth model. It suggests also effective strategies to design in vivo experiments in animals with potential saving of time and resources. For example, the drug concentration threshold for the tumor eradication, the delay between drug administration and tumor regression, and a time index that measures the efficacy of a treatment are derived and discussed. The model has already been employed in several drug discovery projects. Its application on a data set coming from one of these projects is discussed in this paper.

Animals↗