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Gilloteaux J.,University of Namur | Ruffo C.,Northumbria University | Jamison J.M.,The Apatone Development Center | Summers J.L.,The Apatone Development Center
Ultrastructural Pathology | Year: 2016

Ultrastructural data compiled from DU145 human prostate carcinoma cells growing in vivo and, more often in vitro or after treatment by pro-oxidant reactants, can induce and encompass several processes of cell internalization or entosis. These events were observed after tumor cells were essentially undergoing autoschizic injuries and other cell deaths without externalization of phosphatidylserine. Based on other previous observations made on DU145 cells, one hypothesizes that, as a means of survival, tumor cells find sources of nutrients through phagocytosis of apparently intact, injured cells, corpses, and cell debris by cannibalism. These peculiar activities occurred sporadically, in a small population of cells and could be dictated by their widely adapted energetic metabolism, now impaired, either due to the location of the cells in the growing tumors or in vitro as a result of this pro-oxidant anticancer treatment causing damage and abolishing their adapted metabolism. © 2016 Taylor & Francis Source

Gilloteaux J.,University of Namur | Bhalla A.,Northumbria University | Faour O.,Northumbria University | Jamison J.M.,The Apatone Development Center
Ultrastructural Pathology | Year: 2016

The intracellular or intracytoplasmic lumen (IL) is an enigmatic histological structure that occurs in various tumor cells. A reassessment of diverse ILs fine-structure micrographs obtained out of previous studies encompassing the human prostate carcinoma (DU145) cell line and xenotransplanted carcinomas enabled us to propose aspects of ILs’ development in cancer cells: a combination of altered expressions in intercellular contacts and their cytoskeletal components would favor a disarray of self-apical polarity orientation; those defects, associated with a local, entwined enriched membranous structures growing as microvilli-like formations out of a disrupted endoplasm and trans-Golgi sorting, create ILs in cells’ perikarya. These misplaced intracytoplasmic domains can become enlarged through spaces made between the finger-like structures by accruing membranes of coalescent intracytoplasmic vesicles then adding microvilli and glycocalyx to constitute ILs. Cationic mucins added with or without a progressive or total loss of microvilli and content generate signet or ring cell, while ILs enlarge. Variable build-ups of these cells’ populations in carcinomas result in architectural mix up of adjacent cells around these voids, misconstrued as new lumen, and establish a “cribriform” tumor pattern that often implies a poor cancer prognosis. Alternatively, cytotoxic changes caused by anticancer pro-oxidant treatment favor membrane alterations and exaggerate the ILs in xenotransplants into intracellular crypts that accompany other tumor degenerative changes. © 2016 Taylor & Francis Source

Gilloteaux J.,Northumbria University | Jamison J.M.,The Apatone Development Center | Neal D.,The Apatone Development Center | Arnold D.,Waldo County Health Care Inc. | And 2 more authors.
Anatomical Record | Year: 2013

Implanted human, androgen-independent prostatic carcinoma cells (DU145) into athymic (NCr nu/nu) mice produce diverse tumors on the peritoneal surfaces of many organs. Light and ultrastructural observations show that the mesothelial covering these surfaces are typically microvilli-coated, squamous cells or secretory cuboidal cells. The peritoneal regions colonized by tumors lack mesothelial cells and are covered by actively replicating carcinoma cells that grow as poorly differentiated cell clusters made of cell aggregates to somewhat compact spheroids covered with pleiomorphic microvilli and containing an undifferentiated vascular supply. These xenografts clusters invade the diaphragm and develop into tumors with both a basal solid aspect and an upper region of cribriform morphology. Furthermore, each tumor contains two cell types: (1) a poorly differentiated clear cell type, which grows into intraperitoneal tumors and (2) a large, basophilic cell type, which invades the peritoneal stroma of organs, including of the diaphragm. © 2012 Wiley Periodicals, Inc. Source

McGuire K.,The Apatone Development Center | Jamison J.,The Apatone Development Center | Gilloteaux J.,Northumbria University | Summers J.L.,The Apatone Development Center
Journal of Cancer Science and Therapy | Year: 2013

Introduction: Vitamin C (VC), Vitamin K3 (VK3) and the combination (VC:VK3) were evaluated against human bladder cancer cell lines RT-4 and T24 to evaluate their synergistic anticancer activity. Methods/Results: An MTT assay compared a 1hr pulsed versus a 5hr continuous exposure. VC:VK3 was synergistic, increasing the antitumor activity 12-to 24 fold for RT-4 cells. VC:VK3 pulsed versus continuous exposure produced comparable CD50 values, indicating a triggered response involving a catalase reversible redox mechanism generating hydrogen peroxide. Hydrogen peroxide production caused lipid peroxidation and depletion of cellular thiols. ATP levels were measured over 5hrs to determine metabolic effects where VC:VK3 caused a unique spike in ATP levels. Though the cause of the ATP spike is unknown a possible mechanism is a shunt formed around a defective region of complex III of the ETC from coenzyme Q to cytochrome c, producing a shift from glycolytic to oxidative metabolism and a diminution of lactic acidosis. Analysis of mitochondrial and extra mitochondrial calcium levels revealed a unique calcium pattern for RT4 cells treated with CD90 doses of VC, VK3 or VC:VK3. Conclusion: VC:VK3 was able to cause autoschizic cell death through oxidative stress, thiol depletion, lipid peroxidation, modification of ATP levels and calcium regulation. Because of these results, VC:VK3 was granted orphan drug status for the treatment of metastatic or locally advanced, inoperable transitional cell carcinoma of the urothelium (stage III and IV bladder cancer). Efforts are underway to conduct a phase II clinical trial for this indication. © 2013 McGuire K, et al. Source

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