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An evaluation of anti-cancer activities of Hyaenanche Globosa Lamb. (Euphorbiaceae) and Maytenus Procumbens (L.F.) Loes. (Celastraceae)Momtaz, Saeideh 25 May 2013 (has links)
Written records about medicinal plants date back at least 5,000 years to the Sumerians. The objected plants for present investigation were indigenous to South Africa and as explored, only a few biological studies were found on the previous studies on Hyaenanche globosa and Maytenus procumbens. Phytochemical studies of the ethanol extract of the fruits of H. g/obosa (F.E) resulted in isolation of two known pure sesquiterpene lactones; 'tutin 1' and 'hyenanchin 2'. The crude extract and its isolated constituents were tested on four cancerous and a normal cell lines. F.E exhibited the highest antiproliferative activity on Hela cells which followed by Caco-2 cells. None of the isolated compounds were found to be toxic to the cells tested in this experiment. F.E demonstrated potent inhibition of DPPH radical activity similar to vitamin C. 'Tutin 1' and 'hyenanchin 2' were found with marginal antioxidant activity of which 'compound 1' presented more potent activity than 'compound 2'. The amounts of ROS radicals formed by pure compounds (1 and 2) were not significantly higher than those of controls. This is the first report on phytochemical index, anticancer, antioxidant and antibacterial properties of F.E and its purified compounds. The possible biochemical activities of the acetonic/ethanolic extract of the leaves of Maytenus procumbens (L.M.P), and its isolated compounds were investigated in the present study. L.M.P showed IC50 values of 68.79, 51.22, 78.49, 76.59 and 76.64 ì/ml on Caco-2, Hela, HT29, NIH3T3 and T47D cells by use of MTT cytotoxicity assay. Bioassay guided fractionation led to the isolation and identification of two new triterpenes: '30-hydroxy-11á-hydroxy-18â-olean-12-en-3-one 3' and '30-hydroxy-11á-methoxy- 18â-olean-12-en-3-one 5'. In addition, a known terpenoid: 'asiatic acid 4' was purified. Due to the unavailability of sufficient amount of 'asiatic acid 4', this compound was not tested. Pure compounds 3 and 5 exhibited the most cytotoxicity against Hela cells and were further investigated for their abilities for induction of apoptosis (at the concentration of their IC sub>50) in Hela cells using flow cytometric method. Both compounds induced apoptosis up to 73.20%, (compound 3) and 20.40% (compound 5) in Hela cells versus control group (0.40%). Antioxidant/oxidative properties of L.M.P and its isolated compounds were investigated using extracellular (DPPH), and intracellular reactive oxygen species (ROS) assays. L.M.P and the isolated compounds exhibited marginal DPPH discoloration. Experimental samples represented a time and concentrationdependent function of ROS formation in Hela cells. ROS generation might be a part of the mechanisms by which compounds 3 and 5 induced apoptosis in Hela cells. It can therefore be concluded that the active components in L.M.P might serve as a mediator of the reactive oxygen scavenging system and have the potential to act as a prooxidant and an antioxidant, depending on the biological environment of the cells. There is no report until date on phytochemical index, anticancer, antioxidant and antibacterial properties of L.M.P and its isolated compounds. / Thesis (PhD)--University of Pretoria, 2012. / Plant Science / unrestricted
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A baseline evaluation of the cytotoxicity of gold nanoparticles in different types of mammalian cells for future radiosensitization studiesDe Bruyn, Shana January 2020 (has links)
Magister Scientiae (Medical Bioscience) - MSc(MBS) / Recently nanoparticles (NPs) have been introduced and used in combination with therapeutic approaches to develop nanotechnology-enabled medicine. These nanostructures allow for the exploitation of the physiochemical properties which may be beneficial in cancer treatment. The use of NPs in nanomedicine has proven successful in modern chemotherapeutics and has demonstrated promising potential in in vivo and in vitro radiosensitization studies. This is a baseline study aimed to determine the cytotoxic effects of AuNPs for potential radiosensitization analysis. The study analysed the effects of different AuNP sizes (30, 50 and 80nm), concentrations (5, 10 and 15 μg/ml) over various time periods in CHOK1 and A549 cells.
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CT1 and CT3 Mediated Apoptosis of MCF7 and SKBr3 Breast Cancer Cells via Extrinsic Apoptotic PathwayLocke, Autumn, Akinbote, Olasunkanmi, Harding, Jeanna, Torrenegra, Ruben, Bielski, Magdalena, Belcher, Dewey, Aramburo, Jacqueline, Hagood, Kendra Lyndsey, Hackworth, Keagan, Palau, Victoria 25 April 2023 (has links)
Breast cancer is the second most common cancer in women in the United States, accounting for approximately 30% of newly diagnosed female cancers every year. In 2023, it is estimated that around 297,790 invasive breast cancers will be diagnosed as new cases with nearly 43,700 women deaths. The average lifetime risk of a woman in the United States accruing a breast cancer diagnosis is approximately 13%, meaning that there is a 1 in 8 chance of developing breast cancer. Classification of breast cancers is distinguished based on the presence of three receptors: HER2, estrogen, and progesterone. Absence of these receptors is categorized as triple negative breast cancer and accounts for about 15% of all breast cancers, thus is the most aggressive and difficult to treat. In this study, research involving two flavonoids, CT1 and CT3 show cytotoxic effects against cell lines MCF7 (ER+, PR+, HER2-) and SKBr3 (ER-, PR-, HER2+), that represent the most common breast cancers. CT1 and CT3 were extracted from the leaves of Chromolaena tacotana using a Soxhlet extractor, followed by isolation and purification by chromatography. The cells were seeded and then treated with CT1 or CT3 at concentrations of 5, 10, 20, 40 and 80 mM for cytotoxicity assays, and 40mM for analysis of mechanism of action via immunoblotting and TUNEL. These two flavonoids differ on the presence of a double bond between positions 2 and 3. At the concentrations tested, CT1 has cytotoxic activity against MCF7 but no significant effect on SKBr3, while CT3 has cytotoxic activity against SKBr3 but not on MCF7. CT1 and CT3 target the activated forms of ERK, c-JUN and SP6; however, the effect of CT1 appears to be significantly stronger than CT3 and does not involve the survival pathway. CT1 and CT3 inhibit cell viability in MCF7 and SKBr3 breast cancer cells by activating an extrinsic apoptotic pathway. Additional studies using a triple negative breast cancer cell line has shown that this activation is independent of the presence of estrogen and progesterone receptors or the upregulation of HER2.
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Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compoundsOrtuzar, N., Karu, K., Presa, Daniela, Morais, Goreti R., Sheldrake, Helen M., Shnyder, Steven D., Barnieh, Francis M., Loadman, Paul, Patterson, Laurence H., Pors, Klaus, Searcey, M. 05 October 2023 (has links)
Yes / The duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation. / The authors would like to thank Yorkshire Cancer Research (Program grant B381PA) for supporting our work focused on exploring CYPs as targets for prodrug development. The human recombinant CYP1A1 was a gift from Prof Emily E. Scott, University of Michigan; the enzyme was produced via NIH funded grant (R37 GM076343).
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Cisplatin Cytotoxicity is Unaltered by BCL-2 ExpressionSrivastava, Anupma 04 1900 (has links)
A major challenge in cancer therapy is the emergence of acquired resistance to a wide range of chemotherapeutic drugs with unrelated structures and activities. Possible mechanisms to explain drug resistance are induction of efflux pumps, activation of scavenging pathways and/or changes in the oncogene status of a cell. A number of studies have shown that overexpression of Bcl-2 confers resistance by preventing drug induced apoptosis. In this thesis, Madin Darby canine kidney epithelial (MOCK) cells were used to investigate the relationship between cisplatin resistance and Bcl-2 expression. In our studies overexpression of Bcl-2 was sufficient in preventing apoptosis induced by serum deprivation. However, treatment with varying cisplatin doses did not induce an apoptotic response. Electron microscopy and in situ DNA end labelling experiments show changes distinct from those associated with serum deprivationinduced apoptosis. Survival as assessed by DNA fluorometry and clonogenic assays clearly demonstrate that the overexpression of Bcl-2 fails to protect against the cytotoxic effects of cisplatin in MOCK cells. Our results show that cisplatin induces a form of cell death distinct from apoptosis and suggests that multiple pathways to cell death exist which are differentially regulated in a cell type-specific and stimuli-specific fashion. / Thesis / Master of Science (MS)
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Genotoxicity and cytotoxicity of zinc oxide and titanium dioxide in HEp-2 cells.Osman, Ilham F., Baumgartner, Adolf, Anderson, Diana, Cemeli, Eduardo, Fletcher, Jonathan N. January 2010 (has links)
Yes / Aims: The rapidly growing industrial and medical use of nanomaterials, especially zinc oxide and titanium dioxide, has led to growing concerns about their toxicity. Accordingly, the intrinsic genotoxic and cytotoxic potential of these nanoparticles have been evaluated. Materials & methods: Using a HEp-2 cell line, cytotoxicity was tested along with mitochondrial activity and neutral red uptake assays. The genotoxic potential was determined using the Comet and the cytokinesis-blocked micronucleus assays. In addition,tyrosine phosphorylation events were investigated. Results & conclusion: We found concentration- and time-dependent cytotoxicity and an increase in DNA and cytogenetic damage with increasing nanoparticle concentrations. Mainly for zinc oxide, genotoxicity was clearly associated with an increase in tyrosine phosphorylation. Our results suggest that both types of nanoparticles can be genotoxic over a range of concentrations without being cytotoxic. / Embargo ended 3/11/ 2011
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Increasing anti-cancer activity with longer tether lengths of group 9 Cp* complexesLucas, S.J., Lord, Rianne M., Basri, A.M., Allison, Simon J., Phillips, Roger M., Blacker, A.J., McGowan, P.C. 17 February 2016 (has links)
Yes / Here in, we report the cytotoxicity of both rhodium and iridium functionalised Cp* analogues of the [Cp*MCl2]2 dimers. The functionalised dimers contain a hydroxy tethered arm of differing carbon length. These show promising IC50 values when tested against HT-29, A2780 and cisplatin-resistant A2780cis human cancer cell lines, with the cytotoxicity improving proportionally with an increase in carbon tether length of the Cp* ring. The most promising results are seen for the 14-carbon Cp* tethered rhodium (2d) and iridium (3b) complexes, which show up to a 24-fold increase in IC50 compared to the unfunctionalised [Cp*MCl2]2 dimer. All complexes were potent inhibitors of purified thioredoxin reductase suggesting that disruption of cellular anti-oxidant function is one potential mechanism of action.
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Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compoundsOrtuzar, N., Karu, K., Presa, Daniela, Morais, Goreti R., Sheldrake, Helen M., Shnyder, Steven, Barnieh, Francis M., Loadman, Paul, Patterson, Laurence H., Pors, Klaus, Searcey, M. 06 July 2021 (has links)
Yes / The duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation.
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Activation and effector function of unconventional acute rejection pathways studied in a hepatocellular allograft modelHorne, Phillip Howard, January 2007 (has links)
Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 283-321).
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Neonatal T Cell Responses are Highly Plastic: I. Neonates Generate Robust T Cell Responses against Alloantigens II. Functional Capabilities of Neonatal RTE are more Diverse than Adult RTEOpiela, Shannon Jacqueline 28 July 2008 (has links)
Neonatal immune responses are typically deficient against a wide variety of antigens, including alloantigens, vaccine antigens, and infectious agents. These responses are characterized by Th2-skewed cytokine production, and deficient Th1 and cytotoxic responses. However, these deficient responses can be boosted to adult levels by the use of strong, Th1 promoting agents. This demonstrates that neonates are capable of developing mature immune responses under specific conditions. Using two different murine models, we have found that neonates develop robust Th and cytotoxic responses, which under some antigenic conditions significantly exceed those of adults. First, using a model of early life exposure to noninherited maternal antigens (NIMA), we found that murine neonates develop robust in vivo cytotoxic responses to low doses of alloantigens. Importantly, primary in vivo cytotoxic responses to alloantigen developed during the neonatal period, and persisted into adulthood. Neonates developed similar memory cytotoxic responses to donor spleen cells, bone marrow, and stem cell-enriched (Lin-) bone marrow cells, suggesting that the exposure dose is more important than the type of transplanted donor cell for the development of cytotoxicity. NIMA-exposed neonates also developed vigorous primary and memory allospecific Th1/Th2 responses which exceeded the responses of adults. These findings suggest that early exposure to low levels of NIMA may lead to long term immunological priming of all arms of T cell adaptive immunity. Second, we characterized the phenotype and function of neonatal recent thymic emigrants (RTE). RTE are the predominant cell type in murine neonates, and are present at higher frequencies within the neonatal CD4+ compartment than in adults. Our data demonstrate that RTE from murine neonates and adults are phenotypically and functionally distinct. In particular, although the magnitude of RTE cytokine responses from both age groups is dependent on the conditions of activation, neonatal RTE consistently exhibited higher levels of effector cytokine production than adult RTE. In particular, activation of neonatal RTE in the presence of IL-7 lead to greatly increased IFNgamma production, while adult responses were not altered. Overall, neonatal RTE responses were more plastic than those of adult RTE, as both Th1 and Th2 responses were altered in neonates using various activation conditions, while only Th2 responses were consistently changed in adults. Finally, in contrast to adult RTE, neonatal RTE proliferated in response to IL-7 stimulation at very early timepoints. This was associated with faster kinetics of IL-7Ralpha downregulation and higher levels of pSTAT5 in neonatal RTE. These quantitative and qualitative differences in neonatal RTE populations may largely explain the diverse responses that are elicited in neonates in response to different antigens, especially under those conditions in which Th1 responses are enhanced (i.e., exposure to NIMA alloantigens). Taken together, these data demonstrate that neonatal T cell responses are actually highly plastic, instead of intrinsically deficient. Furthermore, if given optimal stimulation conditions, neonatal responses can actually exceed those produced by adults.
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