FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2515659751> ?p ?o ?g. }

• W2515659751 abstract "Abstract Background: Cytogenetic and molecular aberrations have improved risk stratification of acute myeloid leukemia (AML) patients, however survival continues to be low (40-50%) and current therapy primarily includes high dose cytotoxic chemotherapy with or without allogeneic stem cell transplant. In AML, metabolomic analysis has identified key differences in glycolysis, gluconeogenesis and tri-carboxylic acid (TCA) pathways between normal and AML cells. Monotherapy with mitochondrial inhibitors like Metformin have met with little success since cancer cells use glycolytic escape mechanisms to overcome the decreased mitochondrial oxidative phosphorylation. Here we demonstrate a novel therapeutic approach for overcoming this route of Metformin resistance. Methods: Metformin, a well-established anti-diabetic drug, is a strong inhibitor of mitochondrial respiration and is also considered an inhibitor of mTOR signaling acting via AMPK activation. Despite its therapeutic potential, cytotoxicity of AML cells with Metformin alone at achievable plasma levels (10-20 mM) is modest due in part to increased glycolytic ATP production as a bypass mechanism. This has limited the effectiveness of Metformin in AML and led us to investigate mechanisms for reversal of this resistance mechanism to improve the pre-clinical efficacy. 6-Benzylthioinosine (6-BT) is a small molecule that we have shown depletes ATP and can cause differentiation in myeloid leukemia cells (at 10µM concentration) with minimal toxicity to normal cells (LD50 >100µM) (Wald et al. Cancer Res, 2008). To improve on cytotoxicity seen with Metformin, we hypothesized that the combination of 6-BT and Metformin would enhance cytotoxicity in AML. The combination of Metformin (10mM) and 6-BT (10 µM) were tested alone or combined. We compared the effects of the combination treatment on mTOR signaling and caspase-3 activation. We also measured changes in reactive oxygen species (ROS), intracellular ATP, extracellular glucose levels and GLUT-1 expression. Glycolytic flux was measured by Extracellular Acidification Rate (ECAR) and oxidative phosphorylation was measured by Oxygen Consumption Rate (OCR) using Seahorse XF Analyzer. All experiments were performed in triplicate and Student’s two tailed t-test was used to calculate p-values (less than 0.05 were considered to be statistically significant). Results: Metformin and 6-BT alone caused inhibition of cell growth (< 3-fold) and modest cytotoxicity (10-40%, SD ± 6.3%) in all AML cell lines tested (MV4-11, MOLM-14, OCI-AML3, Nomo-1 and THP-1). However the combination of 6-BT with Metformin resulted in marked growth inhibition (30-50 fold) and cytotoxicity (90-100%, SD ± 8.3%) in monocytic AML cell lines (MV4-11 and MOLM-14) within 48 hours of exposure, which was partially dependent on caspase-3 induction. Apoptosis induction was also detected by Annexin V assay. Cytotoxic effects were independent of mTOR inhibition since AZD8055 showed no synergy with the 6-BT or the combination. 6-BT has structural similarity with 6-Mercaptopurine (6-MP), however the combination of Metformin and 6-MP also showed no synergy. 6-BT combined with Metformin caused significant (50-70%) reduction in intracellular ATP levels in the monocytic AML lines without significant extracellular glucose depletion suggestive of glycolytic inhibition. As expected, Metformin significantly suppressed oxidative phosphorylation as evident by near complete inhibition of OCR (<0 pmols/min) and subsequent reduction of ROS to levels <40% of normal. 6-BT alone showed significant suppression of glycolysis with reduction in ECAR but more strikingly reduced by 50% the glycolytic flux normally induced by Metformin and was accompanied by a 50% reduction in the mRNA levels for the glucose transporter GLUT-1. Conclusions: The anti-tumor and metabolic effects of Metformin have been limited by the metabolic reprogramming within cells that result in low cytotoxicity. Here we show that the novel combination of 6-BT and Metformin targets this metabolic bypass mechanism resulting in increased cell death. This is the first demonstration that 6-BT, a drug that is selectively taken up and phosphorylated by AML cells, can exert cytotoxicity involving down modulation of glycolysis. We propose that the combination of 6-BT and Metformin represents a new therapeutic strategy that warrants further testing in primary patient samples. Disclosures No relevant conflicts of interest to declare." @default.
• W2515659751 created "2016-09-16" @default.
• W2515659751 creator A5004390044 @default.
• W2515659751 creator A5006142419 @default.
• W2515659751 creator A5055390157 @default.
• W2515659751 creator A5071691754 @default.
• W2515659751 creator A5085618254 @default.
• W2515659751 creator A5085649615 @default.
• W2515659751 creator A5089187025 @default.
• W2515659751 date "2014-12-06" @default.
• W2515659751 modified "2023-09-27" @default.
• W2515659751 title "Synergistic Cytotoxicity in Acute Myeloid Leukemia By Combined Treatment with Metformin and 6-Benzylthioinosine" @default.
• W2515659751 doi "https://doi.org/10.1182/blood.v124.21.3754.3754" @default.
• W2515659751 hasPublicationYear "2014" @default.
• W2515659751 type Work @default.
• W2515659751 sameAs 2515659751 @default.
• W2515659751 citedByCount "0" @default.
• W2515659751 crossrefType "journal-article" @default.
• W2515659751 hasAuthorship W2515659751A5004390044 @default.
• W2515659751 hasAuthorship W2515659751A5006142419 @default.
• W2515659751 hasAuthorship W2515659751A5055390157 @default.
• W2515659751 hasAuthorship W2515659751A5071691754 @default.
• W2515659751 hasAuthorship W2515659751A5085618254 @default.
• W2515659751 hasAuthorship W2515659751A5085649615 @default.
• W2515659751 hasAuthorship W2515659751A5089187025 @default.
• W2515659751 hasConcept C109316439 @default.
• W2515659751 hasConcept C126322002 @default.
• W2515659751 hasConcept C20251656 @default.
• W2515659751 hasConcept C202751555 @default.
• W2515659751 hasConcept C2778461978 @default.
• W2515659751 hasConcept C2778729363 @default.
• W2515659751 hasConcept C2779306644 @default.
• W2515659751 hasConcept C2780323712 @default.
• W2515659751 hasConcept C502942594 @default.
• W2515659751 hasConcept C55493867 @default.
• W2515659751 hasConcept C62231903 @default.
• W2515659751 hasConcept C71924100 @default.
• W2515659751 hasConcept C86803240 @default.
• W2515659751 hasConcept C98274493 @default.
• W2515659751 hasConceptScore W2515659751C109316439 @default.
• W2515659751 hasConceptScore W2515659751C126322002 @default.
• W2515659751 hasConceptScore W2515659751C20251656 @default.
• W2515659751 hasConceptScore W2515659751C202751555 @default.
• W2515659751 hasConceptScore W2515659751C2778461978 @default.
• W2515659751 hasConceptScore W2515659751C2778729363 @default.
• W2515659751 hasConceptScore W2515659751C2779306644 @default.
• W2515659751 hasConceptScore W2515659751C2780323712 @default.
• W2515659751 hasConceptScore W2515659751C502942594 @default.
• W2515659751 hasConceptScore W2515659751C55493867 @default.
• W2515659751 hasConceptScore W2515659751C62231903 @default.
• W2515659751 hasConceptScore W2515659751C71924100 @default.
• W2515659751 hasConceptScore W2515659751C86803240 @default.
• W2515659751 hasConceptScore W2515659751C98274493 @default.
• W2515659751 hasLocation W25156597511 @default.
• W2515659751 hasOpenAccess W2515659751 @default.
• W2515659751 hasPrimaryLocation W25156597511 @default.
• W2515659751 hasRelatedWork W128310089 @default.
• W2515659751 hasRelatedWork W2046124260 @default.
• W2515659751 hasRelatedWork W2335995018 @default.
• W2515659751 hasRelatedWork W2408171154 @default.
• W2515659751 hasRelatedWork W2472533454 @default.
• W2515659751 hasRelatedWork W2528999970 @default.
• W2515659751 hasRelatedWork W2534792166 @default.
• W2515659751 hasRelatedWork W2548044687 @default.
• W2515659751 hasRelatedWork W2557568345 @default.
• W2515659751 hasRelatedWork W2558474040 @default.
• W2515659751 hasRelatedWork W2583616640 @default.
• W2515659751 hasRelatedWork W2585344417 @default.
• W2515659751 hasRelatedWork W2588517367 @default.
• W2515659751 hasRelatedWork W2756786254 @default.
• W2515659751 hasRelatedWork W2766244738 @default.
• W2515659751 hasRelatedWork W2809553902 @default.
• W2515659751 hasRelatedWork W2965186442 @default.
• W2515659751 hasRelatedWork W3045910496 @default.
• W2515659751 hasRelatedWork W3108351865 @default.
• W2515659751 hasRelatedWork W3153244363 @default.
• W2515659751 isParatext "false" @default.
• W2515659751 isRetracted "false" @default.
• W2515659751 magId "2515659751" @default.
• W2515659751 workType "article" @default.