The Effect of Cisplatin on the Role of Proprotein Convertases (PCs) in Human Ovarian Cancer Cells PDF Download
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Author: Hillary Michelle Boulay
Publisher:
ISBN:
Category : Ovaries
Languages : en
Pages : 0
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Author: Hillary Michelle Boulay
Publisher:
ISBN:
Category : Ovaries
Languages : en
Pages : 0
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Author: Daniel Bassi
Publisher: Morgan & Claypool Publishers
ISBN: 1615044647
Category : Cancer
Languages : en
Pages : 51
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Gynecological cancers include neoplasias of internal female genital organs, mainly ovarian, endometrial and cervical tumors, and cancers of the external female genital structures. Current scientific evidence indicates that both up- and down-regulation of the expression of PCs are part of the multiple changes occurring in these gynecological tumors. Nevertheless, the physiological significance of this puzzling pattern of PC expression remains elusive. The fact that PCs can activate both pro- and anticarcinogenic substrates may indicate that the nature of the overexpressed substrates in certain cancer types could determine the final outcome; i.e., slowing or accelerating cancer development.
Author: Janet Kwan
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Proprotein convertases (PC) are proteases implicated in the regulation of mediators crucial for cancer growth and progression. The literature suggests that over-expression of some PCs contributes to tumorigenesis, invasion and metastasis in vivo; but evidence of the contrary also exists, where PC inhibition enhances cell migration and lung metastasis. The balance of these two opposing outcomes may determine the overall effect of specific PCs, resulting in cancers with increased or decreased aggressiveness. Preliminary data suggests that the expression of several PCs and a chaperone protein 7B2 is altered in human colorectal cancer (CRC) liver metastasis, and we hypothesize that the levels of active PCs in the primary CRC might predict progression and metastasis. To determine the effect of PCs (PACE4, PC5/6, PC7, Furin, PC1/3) and 7B2 in metastatic colon cancer cells, human CRC line HT-29 transfected with shRNA to the given genes was studied. The phenotypic ...
Author: Archie W. Prestayko
Publisher: Academic Press
ISBN: 1483289001
Category : Science
Languages : en
Pages : 544
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Cisplatin: Current Status and New Developments is a collection of papers presented at a symposium sponsored by the University of Alabama in Birmingham Comprehensive Cancer Center and the Bristol Laboratories in Syracuse, ?ew York, and held on September 27-28, 1979, in Atlanta, Georgia. The symposium provided a forum for assessing developments with regards to cisplatin as an anticancer drug, with emphasis on its clinical application in a wide variety of adult and pediatric malignancies as well as the mechanism by which the drug appears to cause tumor cell death. Comprised of 39 chapters, this book begins with a preclinical overview of cisplatin, focusing on its mechanism of action, pharmacology, antitumor activity, analogs, and toxicity. The discussion then turns to the effects of cisplatin on DNA and the possible relationships to cytotoxicity and mutagenicity in mammalian cells; lethal activity of platinum compounds in combination with pyrimidine derivatives; and ultrastructural effects of cisplatin. Subsequent chapters focus on the rationale of combination chemotherapy; toxic side effects of platinum analogs; radiopharmacokinetics of cisplatin; and the use of cisplatin for the treatment of malignancies such as ovarian cancer and advanced adenocarcinoma of the prostate. This monograph will be useful to oncologists and pharmacologists.
Author: Shadia Mohamed Al Bahlani
Publisher:
ISBN:
Category : Apoptosis
Languages : en
Pages : 0
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Author: Mohammad Reza Abedini
Publisher:
ISBN:
Category : Apoptosis
Languages : en
Pages : 416
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Author: Xiaowei Sun
Publisher:
ISBN:
Category :
Languages : en
Pages :
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"Cancer is a leading cause of death worldwide and accounts for about one fifth of all death in the Western world. In 2008, nearly 12.7 million new cancer cases and 7.6 million cancer deaths occurred worldwide. The development of cancer is a multistage process, during which cells acquire a series of mutations that eventually lead to unrestrained cell growth, evasion of cell death, angiogenesis, invasion of the surrounding tissue and finally spreading to other parts of the body. The mammalian proprotein convertases (PCs) constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin. They have been associated with cancer since the early 1990s. By processing cancer-associated factors, PCs are believed to play key roles in almost every step of cancer development. Seven of these PCs (PC1, PC2, furin, PC4, PC5/6, PACE4 and PC7) activate, or less frequently inactivate, a wide variety of substrates, including hormones, growth factors, receptors, adhesion molecules, angiogenic factors, metalloproteases. Among these substrates, some of them are key factors controlling cancer progression and metastasis. The last member of this family proprotein convertase subtilisin kexin 9 (PCSK9) only cleaves itself and participates in maintaining the levels of cholesterol, which was shown to have impacts on cancer incidence.In this thesis, I focused on the role of two PCs, PC5/6 and PCSK9, in cancer development. I first showed that PC5/6 is systematically down-regulated in human and mice intestinal tumors. In ApcMin/+ mice which are a colonic cancer model and develop numerous adenocarcinomas along the intestinal tract, the specific knockout of PC5/6 in the intestine and colon leads to higher number of tumors, particularly in duodenum. This suggests that PC5/6 plays a protective role against tumorigenesis in the intestine. Although PC5/6 is protective in intestinal cancer, it has been shown to promote tumor progression in other cancer types e.g., brain and skin. Interestingly, PC5/6 is inhibited by some natural inhibitors, the latent TGFbeta binding proteins 2 and 3 (LTBP-2, -3). These two proteins reduce the enzymatic activity of PC5/6A and reduce the bio-availability of PC5/6A by sequestering the zymogen proPC5/6 in the extracellular matrix. Finally, I demonstrated that the lack of PCSK9 leads to a significantly lower level of liver metastasis of melanoma cells. This cancer protective effect is due to low plasma cholesterol levels as well as high apoptosis in liver stroma and metastasized tumors that are associated with PCSK9 deficiency.In summary, the present cumulative data define some of the in vivo roles of PC5/6 and PCSK9 in cancer and should enhance our appreciation of the physiological impact of PC inhibition." --
Author: Jimmy Belotte
Publisher:
ISBN:
Category : Oncology
Languages : en
Pages : 114
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Epithelial ovarian cancer is the deadliest of all gynecologic cancers with an estimated 22,280 new cases and 14,240 deaths expected in 2016 in the US alone. This high mortality rate can be partially attributed to a lack of universal screening and the development of resistance to the recommended chemotherapeutics. Typically, the treatment of ovarian cancer requires both cytoreductive surgery (CRS) and platinum/taxane combination chemotherapy. Initially, 500́380% of patients with advanced disease will achieve complete clinical response. Unfortunately, most will relapse within 18 months with chemoresistant disease. Thus, understanding the mechanisms of platinum resistance is critical in order to improve the care of ovarian cancer patients. Several theories to explain cisplatin resistance have been proposed but failed to translate into clinical practice. Typically drug resistance mechanisms are multifactorial but can be broadly categorized as follows: 1) pharmacokinetic, resulting in inadequate intratumor cisplatin concentration, 2) tumor micro-environment, involving membrane transporters by reducing cisplatin uptake or increasing efflux, 3) increased inactivation and sequestration of cisplatin, 4) activation of DNA repair and antiapoptotic mechanisms, 5) decreased autophagy and, 6) cancer-cell specific mechanisms such as: acquired somatic mutations and epigenetic changes and persistence of slow growing cancer stem cells that maintain the cancer phenotype. We have recently characterized EOC tissues and cells to manifest a persistent pro-oxidant state with the upregulation of several key oxidant enzymes including: myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), and nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase with concurrent decrease in apoptosis compared to normal human ovarian tissues and cells.
Author: Sanad M. Z. Alonezi
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Over the last few years, metabolomics has come to play an increasingly important part in many fields of research, notably medical studies. However, there is a dearth of research on metabolomics in the area of ovarian cancer and the increase in anti-cancer (platinum) drug resistance. Thus further studies on the modes of anticancer action and the mechanisms of resistance of ovarian cancer cells at the metabolome level are needed. The aim of this study was to characterise the metabolic profiles of two human ovarian cancer cell lines, A2780 (cisplatin-sensitive) and A2780CR (cisplatin-resistant), in response to their exposure to melittin, cisplatin and melittin-cisplatin combination therapy. It has been suggested that melittin may have potential as an anti-cancer therapy; combining cisplatin and melittin may increase response and tolerability in cancer treatment, as well as reducing drug resistance.The A2780 and A2780CR cell lines were treated with sub-lethal doses of melittin, cisplatin and melittin-cisplatin combination therapy for 24 hours before extraction and global metabolite analysis of cell lysates by LC-MS using a HPLC system. Phenotype MicroArrayTM experiments were also applied in order to test carbon substrate utilisation or sensitivity in both cell lines after exposure to melittin and cisplatin. Data extraction was carried out with MZmine 2.10 with metabolite searching against an in-house database. The data were analysed using univariate and multivariate methods.The changes induced by melittin in the cisplatin-sensitive cells mainly resulted in reduced levels of amino acids in the proline/glutamine/arginine pathway, as well as to decreased levels of carnitines, polyamines, ATP and NAD+. It was necessary to evaluate the effect of a melittin on lipid activities of ovarian cancer cell lines. In order to do so, an LC coupled to an Orbitrap Exactive mass spectrometer using an ACE silica gel column was employed. The two cell lines had distinct lipid compositions, with the A2780CR cells having lower levels of several ether lipids than the A2780 cells. The changes induced by melittin in both cell lines mainly led to a decrease the level of PC and PE. Lipids were significantly altered in both A2780 and A2780CR cells. The observed effect was much more marked in the cisplatin-sensitive cells, suggesting that the sensitive cells undergo much more extensive membrane re-modelling in responsexviito melittin in comparison with the resistant cells. Regarding the metabolic effects of cisplatin on A2780 cells, these mainly resulted decreased levels of acetylcarnitine, phosphocreatine, arginine, proline and glutathione disulfide, as well as to increased levels of tryptophan and methionine. A number of metabolites were differently affected between the A2780 and A2780CR cells following cisplatin treatment, with A2780CR cells presenting increased levels of lysine, and decreased levels of N-acetyl-glutamate, oxoglutarate and 2-oxobutanoate compared to sensitive cells. However, when the combination treatment was applied, there were significant changes in both cell lines, mainly resulting in a reduction of levels of citrate cycle, oxidative phosphorylation, purine, pyrimidine and arginine/proline pathways. The combination of melittin with cisplatin has a synergistic effect when targeting these pathways. The melittin-cisplatin combination had stronger effect on A2780 cell lines than it had on those of A2780CR.Overall, this study suggests that melittin may have some potential as an adjuvant therapy in cancer treatment. A global metabolomics approach can be a useful tool for evaluating the pharmacological effects of anti-cancer compounds or synergetic sensitisers using mass spectrometry.
Author: Seyed F. Hosseini Shirazi
Publisher:
ISBN:
Category : Cancer
Languages : en
Pages : 336
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There is a strong correlation between cytotoxicity of the platinum species and their cellular uptake (r = 0.997). Infrared spectroscopy (IR) was done on OV 2008 cells after one hour exposure to different concentrations of species. IR data suggest that MP induced more cellular changes than the other species. While bands of all CP metabolites attributed to the phosphate and amide II stretching indicate a frequency shift and intensity variation, those of methyl and methylene stretching vibrations of the cell membrane seem to be hardly affected. In conclusion, CP and its metabolites have different effects on OV 2008 cells.
