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Metabolically Supported Chemotherapy

Kathrin Renner, Anton Seilbeck, Nathalie Kauer, Ines Ugele, Peter J Siska, Christina Brummer, Christina Bruss, Sonja-Maria Decking, Matthias Fante, Astrid Schmidt, Kathrin Hammon, Katrin Singer, Sebastian Klobuch, Simone Thomas, Eva Gottfried, Katrin Peter, Marina Kreutz
The accelerated metabolism of tumor cells, inevitable for maintaining high proliferation rates, is an emerging target for tumor therapy. Increased glucose and lipid metabolism as well as mitochondrial activity have been shown in solid tumors but also in leukemic cells. As tumor cells are able to escape the blockade of one metabolic pathway by a compensatory increase in other pathways, treatment strategies simultaneously targeting metabolism at different sites are currently developed. However, the number of clinically applicable anti-metabolic drugs is still limited...
2018: Frontiers in Pharmacology
Juliette Servante, Jasper Estranero, Lisethe Meijer, Rob Layfield, Richard Grundy
Brain tumors are the leading cause of cancer-related death in children and are the most challenging childhood cancer in relation to diagnosis, treatment, and outcome. One potential novel strategy to improve outcomes in cancer involves the manipulation of autophagy, a fundamental process in all cells. In cancer, autophagy can be thought of as having a "Janus"-like duality. On one face, especially in the early phases of cancer formation, autophagy can act as a cellular housekeeper to eliminate damaged organelles and recycle macromolecules, thus acting as tumor suppressor...
October 16, 2018: Oncotarget
Akihiko Sakamoto, Shunsuke Kunou, Kazuyuki Shimada, Makoto Tsunoda, Tomohiro Aoki, Chisako Iriyama, Akihiro Tomita, Shigeo Nakamura, Fumihiko Hayakawa, Hitoshi Kiyoi
Cancer-associated fibroblasts (CAFs) are a key component in the tumor microenvironment and play functional roles in tumor metastasis and resistance to chemotherapies. We have previously reported that CAFs isolated from lymphoma samples increase anaerobic glycolysis and decrease intracellular production of reactive oxygen species, promoting the survival of tumor cells. Here, we analyzed the mechanisms underlying this support of tumor-cell survival by CAFs. As direct contact between lymphoma cells and CAFs was not indispensable to survival support, we identified that the humoral factor pyruvate was significantly secreted by CAFs...
November 13, 2018: Cancer Science
James Gilmore, Alberto Bernareggi
NEPA is the first fixed-combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant (netupitant; 300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (palonosetron; 0.50 mg). This study evaluated the pharmacokinetic profiles of netupitant and palonosetron. The pharmacokinetic profiles of both drugs were summarized using data from phase 1-3 clinical trials. netupitant and palonosetron have high absolute bioavailability (63%-87% and 97%, respectively). Their overall systemic exposures and maximum plasma concentrations are similar under fed and fasting conditions...
November 9, 2018: Journal of Clinical Pharmacology
Alasdair J Scott, Claire A Merrifield, Jessica A Younes, Elizabeth P Pekelharing
There is a growing appreciation of the role of the human microbiota in the pathophysiology of cancer. Pre-, pro- and synbiotics are some of the best evidenced means of manipulating the microbiota for therapeutic benefit and their potential role in the prevention and treatment of cancer has garnered significant interest. In this review, we discuss how these agents may have oncosuppressive effects by maintaining intestinal barrier function, immunomodulation, metabolism and preventing host cell proliferation. We highlight the epidemiological and trials-based evidence supporting a role for pre-, pro- and synbiotics in the prevention of cancer...
2018: Ecancermedicalscience
Géraldine Gentric, Yann Kieffer, Virginie Mieulet, Oumou Goundiam, Claire Bonneau, Fariba Nemati, Ilse Hurbain, Graca Raposo, Tatiana Popova, Marc-Henri Stern, Valérie Lallemand-Breitenbach, Sebastian Müller, Tatiana Cañeque, Raphaël Rodriguez, Anne Vincent-Salomon, Hugues de Thé, Rodrigue Rossignol, Fatima Mechta-Grigoriou
High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic, metabolomic, and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic metabolism, high-OXPHOS HGSOCs rely on oxidative phosphorylation, supported by glutamine and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PGC-1α axis in the metabolic features of high-OXPHOS HGSOC...
September 17, 2018: Cell Metabolism
Ting Bao, Luke J Peppone, Patricia Robinson
There are 15.5 million cancer survivors in the United States because of, in part, improvements in therapy. As a result, there will be an increased burden of long- and late-term complications of cancer care, such as metabolic alterations. These metabolic changes will include alterations in bone resorption, obesity, hypercholesterolemia, and diabetes mellitus. The majority of cancer treatment-related toxicities have focused on endocrine therapy; however, chemotherapy and supportive medications, such as steroids, contribute to the development of these disorders...
May 23, 2018: American Society of Clinical Oncology Educational Book
Meng Zhang, Qing Cong, Xiao-Yan Zhang, Ming-Xing Zhang, Ying-Ying Lu, Cong-Jian Xu
Patients with ovarian cancer frequently develop acquired drug resistance after the long-term chemotherapy, leading to disease progression. Enhanced epithelial-mesenchymal transition (EMT) has been implicated in chemoresistance of ovarian cancer cells; however, the molecular mechanisms involved are largely undefined. Pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, has been recognized as a gatekeeper of the Warburg effect, a hallmark of cancer. In this study, the function of PDK1 in cisplatin resistance of ovarian cancer in terms of growth and EMT was investigated...
September 19, 2018: Journal of Cellular Physiology
Ismael da Silva, Rene da Costa Vieira, Carolina Stella, Edson Loturco, André Lopes Carvalho, Carlos Veo, Cristovam Neto, Sandra M Silva, Paulo D'Amora, Marcia Salzgeber, Delcio Matos, Celso R Silva, Jose R Oliveira, Iara Rabelo, Patricia Yamakawa, Rui Maciel, Rosa Biscolla, Maria Chiamolera, Renato Fraietta, Felipe Reis, Marcelo Mori, Dirce Marchioni, Antonio Carioca, Gustavo Maciel, Renato Tomioka, Edmund Baracat, Clovis Silva, Celso Granato, Ricardo Diaz, Bruno Scarpellini, Daniel Egle, Heidi Fiegl, Irmgard Himmel, Christina Troi, Robert Nagourney
Breast cancer remains a leading cause of morbidity and mortality worldwide yet methods for early detection remain elusive. We describe the discovery and validation of biochemical signatures measured by mass spectrometry, performed upon blood samples from patients and controls that accurately identify (>95%) the presence of clinical breast cancer. Targeted quantitative MS/MS conducted upon 1225 individuals, including patients with breast and other cancers, normal controls as well as individuals with a variety of metabolic disorders provide a biochemical phenotype that accurately identifies the presence of breast cancer and predicts response and survival following the administration of neoadjuvant chemotherapy...
August 3, 2018: Oncotarget
Frédéric Picou, Christelle Debeissat, Jérôme Bourgeais, Nathalie Gallay, Elise Ferrié, Amélie Foucault, Noémie Ravalet, Aurore Maciejewski, Nicolas Vallet, Elfi Ducrocq, Lamya Haddaoui, Jorge Domenech, Olivier Hérault, Emmanuel Gyan
Acute Myeloid Leukemia (AML) remains a therapeutic challenge and improvements in chemotherapy are needed. n-3 polyunsaturated fatty acids (PUFAs), present in fish oil (FO) at high concentrations, have antitumoral properties in various cancer models. We investigated the effects of two n-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in AML cell lines and primary AML blasts. EPA and DHA induced a dose-dependent decrease in cell viability in five AML cell lines, which was also observed with FO, but not SO (devoid of n-3 PUFAs) in cell lines and primary leucoblasts...
August 22, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Jennifer H Shepherd, Daniel Howard, Amie K Waller, Holly Rebecca Foster, Annett Mueller, Thomas Moreau, Amanda L Evans, Meera Arumugam, Guénaëlle Bouët Chalon, Eleonora Vriend, Natalia Davidenko, Cedric Ghevaert, Serena M Best, Ruth E Cameron
Platelet transfusions are a key treatment option for a range of life threatening conditions including cancer, chemotherapy and surgery. Efficient ex vivo systems to generate donor independent platelets in clinically relevant numbers could provide a useful substitute. Large quantities of megakaryocytes (MKs) can be produced from human pluripotent stem cells, but in 2D culture the ratio of platelets harvested from MK cells has been limited and restricts production rate. The development of biomaterial cell supports that replicate vital hematopoietic micro-environment cues are one strategy that may increase in vitro platelet production rates from iPS derived Megakaryocyte cells...
November 2018: Biomaterials
Tiago Lobo Ferreira, Tiago Nunes da Silva, Dolores Canário, Maria Francisca Delerue
Ectopic adrenocorticotropic hormone (ACTH) secretion represents 5%-10% of cases of Cushing's syndrome (CS), and approximately 50%-60% of these arise from neuroendocrine lung tumours, including small-cell lung cancer (SCLC). We report a 42-year-old man admitted with hypertension, metabolic alkalosis and severe hypokalaemia. On physical examination, centripetal obesity with 'moon face' and 'buffalo's hump' were identified, and wheezing on left lung was heard. A markedly elevated serum cortisol, ACTH and urine free cortisol production supported the diagnosis of CS...
August 16, 2018: BMJ Case Reports
Lawrence Karsh, Neal Shore, Mark Soloway, Gajanan Bhat, Guru Reddy, Szu-Yun Leu, J Alfred Witjes
Background: Guidelines recommend a single postoperative instillation of intravesical chemotherapy within 24 hours of transurethral resection of bladder tumors (TURBT) in patients with low- and intermediate-risk non-muscle invasive bladder cancer (NMIBC) to reduce recurrence risk. Objective: To evaluate the 2-year recurrence rate (2-YRR) of bladder cancer in randomized patients with Ta, G1-G2 histology who receive TURBT plus apaziquone versus TURBT plus placebo. Methods: Two nearly identical Phase 3, multinational, randomized, double-blind, placebo-controlled trials were conducted in patients with histologically confirmed Ta, G1-G2 NMIBC (Target Population) to evaluate the efficacy/safety of a single instillation of apaziquone post-TURBT...
July 30, 2018: Bladder Cancer
Angelica Macauda, Eleonora Castelli, Gabriele Buda, Matteo Pelosini, Aleksandra Butrym, Marzena Watek, Marcin Kruszewski, Annette Juul Vangsted, Marcin Rymko, Krzysztof Jamroziak, Niels Abildgaard, Eva Kannik Haastrup, Grzegorz Mazur, Rafael Ríos, Artur Jurczyszyn, Daria Zawirska, Marek Dudziński, Małgorzata Raźny, Magdalena Dutka, Waldemar Tomczak, Anna Suska, Agnieszka Druzd-Sitek, Herlander Marques, Mario Petrini, Miroslaw Markiewicz, Joaquin Martinez-Lopez, Lene Hyldahl Ebbesen, Elżbieta Iskierka-Jażdżewska, Juan Sainz, Federico Canzian, Daniele Campa
Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries...
August 6, 2018: British Journal of Haematology
Hae-In Kim, Hyesol Lim, Aree Moon
The incidence and mortality of various cancers are associated with sex-specific disparities. Sex differences in cancer epidemiology are one of the most significant findings. Men are more prone to die from cancer, particularly hematological malignancies. Sex difference in cancer incidence is attributed to regulation at the genetic/molecular level and sex hormones such as estrogen. At the genetic/molecular level, gene polymorphism and altered enzymes involving drug metabolism generate differences in cancer incidence between men and women...
July 1, 2018: Biomolecules & Therapeutics
Catharina Bartmann, Sudha R Janaki Raman, Jessica Flöter, Almut Schulze, Katrin Bahlke, Jana Willingstorfer, Maria Strunz, Achim Wöckel, Rainer J Klement, Michaela Kapp, Cholpon S Djuzenova, Christoph Otto, Ulrike Kämmerer
Background: Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Beta-hydroxybutyrate (3-OHB) is the main physiological ketone body, whose concentration can reach plasma levels of 2-6 mM during KDs or fasting. The impact of 3-OHB on the biology of tumor cells described so far is contradictory. Therefore, we investigated the effect of a physiological concentration of 3 mM 3-OHB on metabolism, proliferation, and viability of breast cancer (BC) cells in vitro...
2018: Cancer & Metabolism
Michael I Koukourakis, Alexandra Giatromanolaki
The anaerobic metabolism of glucose by cancer cells, even under well-oxygenated conditions, has been documented by Otto Warburg as early as 1927. Micro-environmental hypoxia and intracellular pathways activating the hypoxia-related gene response, shift cancer cell metabolism to anaerobic pathways. In the current review, we focus on a major enzyme involved in anaerobic transformation of pyruvate to lactate, namely lactate dehydrogenase 5 (LDH5). The value of LDH5 as a marker of prognosis of cancer patients, as a predictor of response to radiotherapy (RT) and chemotherapy and, finally, as a major target for cancer treatment and radio-sensitization is reported and discussed...
October 16, 2018: International Journal of Radiation Biology
Matteo Allegretti, Beatrice Casini, Chiara Mandoj, Stefania Benini, Laurent Alberti, Mariangela Novello, Elisa Melucci, Laura Conti, Renato Covello, Edoardo Pescarmona, Giuseppe Maria Milano, Alessio Annovazzi, Vincenzo Anelli, Virginia Ferraresi, Roberto Biagini, Patrizio Giacomini
Background: Limited information is available on the applicative value of liquid biopsy (LB) in rare tumors, including Ewing's sarcoma (ES). The accepted precision diagnostics standards would greatly benefit from a non-invasive LB test monitoring pathognomonic gene rearrangements in the bloodstream. Methods: Tissue and blood samples were collected from six and four ES patients, respectively. Plasma was cleared by two successive rounds of centrifugation and stored frozen until RNA extraction by the QIAmp CNA kit...
2018: Therapeutic Advances in Medical Oncology
Julian Hlouschek, Christine Hansel, Verena Jendrossek, Johann Matschke
Pronounced resistance of lung cancer cells to radiotherapy and chemotherapy is a major barrier to successful treatment. Herein, both tumor hypoxia and the upregulation of the cellular antioxidant defense systems observed during malignant progression can contribute to radioresistance. We recently found that exposure to chronic cycling severe hypoxia/reoxygenation stress results in glutamine-dependent upregulation of cellular glutathione (GSH) levels and associated radiation resistance opening novel routes for tumor cell-specific radiosensitization...
2018: Frontiers in Oncology
Jennifer Ose, Akke Botma, Yesilda Balavarca, Katharina Buck, Dominique Scherer, Nina Habermann, Jolantha Beyerle, Katrin Pfütze, Petra Seibold, Elisabeth J Kap, Axel Benner, Lina Jansen, Katja Butterbach, Michael Hoffmeister, Hermann Brenner, Alexis Ulrich, Martin Schneider, Jenny Chang-Claude, Barbara Burwinkel, Cornelia M Ulrich
Folate-mediated one-carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5-fluorouracil (5-FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM-related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM-related genes for associations with overall- (OS) and disease-free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol)...
May 29, 2018: Cancer Medicine
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