Drug repurposing for cancer therapy

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 18, 2024

Abstract Cancer, a complex and multifactorial disease, presents significant challenge to global health. Despite advances in surgical, radiotherapeutic immunological approaches, which have improved cancer treatment outcomes, drug therapy continues serve as key therapeutic strategy. However, the clinical efficacy of is often constrained by resistance severe toxic side effects, thus there remains critical need develop novel therapeutics. One promising strategy that has received widespread attention recent years repurposing: identification new applications for existing, clinically approved drugs. Drug repurposing possesses several inherent advantages context since repurposed drugs are typically cost-effective, proven be safe, can significantly expedite development process due their already established safety profiles. In light this, present review offers comprehensive overview various methods employed repurposing, specifically focusing on treat cancer. We describe antitumor properties candidate drugs, discuss detail how they target both hallmarks tumor cells surrounding microenvironment. addition, we examine innovative integrating with nanotechnology enhance topical delivery. also emphasize role play when used part combination regimen. To conclude, outline challenges associated consider future prospects these transitioning into application.

Language: Английский

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Deuterium metabolic imaging and hyperpolarized 13C-MRI of the normal human brain at clinical field strength reveals differential cerebral metabolism

NeuroImage, Journal Year: 2022, Volume and Issue: 257, P. 119284 - 119284

Published: May 6, 2022

Deuterium metabolic imaging (DMI) and hyperpolarized 13C-pyruvate MRI (13C-HPMRI) are two emerging methods for non-invasive non-ionizing of tissue metabolism. Imaging cerebral metabolism has potential applications in cancer, neurodegeneration, multiple sclerosis, traumatic brain injury, stroke, inborn errors Here we directly compare these at 3 T the first time humans show how they simultaneously probe both oxidative non-oxidative DMI was undertaken 1–2 h after oral administration [6,6′-2H2]glucose, 13C-MRI performed immediately following intravenous injection [1–13C]pyruvate ten nine normal volunteers within each arm respectively. used to generate maps deuterium-labelled water, glucose, lactate, glutamate/glutamine (Glx) spectral separation demonstrated that is feasible T. 13C-HPMRI generated carbon-13 labelled pyruvate, bicarbonate. The ratio 13C-lactate/13C-bicarbonate (mean 3.7 ± 1.2) acquired with higher than equivalent 2H-lactate/2H-Glx 0.18 0.09) using DMI. These differences can be explained by route administering probe, timing ingestion or injection, as well biological uptake cellular physiology between molecules. results demonstrate provide different yet complementary readouts reductive a clinically timescale. Furthermore, clinical field strength ten-minute scan time, it demonstrates its routine tool future.

Language: Английский

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The mitochondrial pyruvate carrier at the crossroads of intermediary metabolism

AJP Endocrinology and Metabolism, Journal Year: 2022, Volume and Issue: 323(1), P. E33 - E52

Published: May 30, 2022

Pyruvate metabolism, a central nexus of carbon homeostasis, is an evolutionarily conserved process and aberrant pyruvate metabolism associated with contributes to numerous human metabolic disorders including diabetes, cancer, heart disease. As product glycolysis, primarily generated in the cytosol before being transported into mitochondrion for further metabolism. entry mitochondrial matrix critical step efficient generation reducing equivalents ATP biosynthesis glucose, fatty acids, amino acids from pyruvate. However, many years, identity carrier protein(s) that remained mystery. In 2012, molecular-genetic identification (MPC), heterodimeric complex composed protein subunits MPC1 MPC2, enabled studies shed light on physiological processes regulated by A better understanding mechanisms regulating transport affected may enable novel therapeutics modulate flux treat variety disorders. Herein, we review our current knowledge MPC, discuss recent advances various tissue cell types, address some outstanding questions relevant this field.

Language: Английский

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Targeting mitochondrial impairment for the treatment of cardiovascular diseases: From hypertension to ischemia-reperfusion injury, searching for new pharmacological targets

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 208, P. 115405 - 115405

Published: Jan. 2, 2023

Language: Английский

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Utilizing nullomers in cell-free RNA for early cancer detection

Cancer Gene Therapy, Journal Year: 2024, Volume and Issue: 31(6), P. 861 - 870

Published: Feb. 14, 2024

Abstract Early detection of cancer can significantly improve patient outcomes; however, sensitive and highly specific biomarkers for are currently missing. Nullomers the shortest sequences that absent from human genome but emerge due to somatic mutations in cancer. We examine over 10,000 whole exome sequencing matched tumor-normal samples characterize nullomer emergence across exonic regions genome. also identify emerging mutational hotspots within tumor genes. Finally, we provide evidence identification nullomers cell-free RNA peripheral blood samples, enabling multiple types. show classification models with an AUC greater than 0.9, including a hepatocellular carcinoma classifier 0.99.

Language: Английский

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The role of glycolysis and lactate in the induction of tumor-associated macrophages immunosuppressive phenotype

International Immunopharmacology, Journal Year: 2022, Volume and Issue: 110, P. 108994 - 108994

Published: June 28, 2022

Language: Английский

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Indole Derivatives as New Structural Class of Potent and Antiproliferative Inhibitors of Monocarboxylate Transporter 1 (MCT1; SLC16A1)

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 66(1), P. 657 - 676

Published: Dec. 30, 2022

The solute carrier (SLC) monocarboxylate transporter 1 (MCT1; SLC16A1) represents a promising target for the treatment of cancer; however, MCT1 modulator landscape is underexplored with only roughly 100 reported compounds. To expand knowledge about modulation, we synthesized library 16 indole-based molecules and subjected these to comprehensive biological assessment platform. All compounds showed functional inhibitory activities against at low nanomolar concentrations great antiproliferative MCT1-expressing cancer cell lines A-549 MCF-7, while were selective over MCT4 (SLC16A4). Lead compound

Language: Английский

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Role of Mitochondrial Transporters on Metabolic Rewiring of Pancreatic Adenocarcinoma: A Comprehensive Review

Cancers, Journal Year: 2023, Volume and Issue: 15(2), P. 411 - 411

Published: Jan. 8, 2023

Pancreatic cancer is among the deadliest cancers worldwide and commonly presents as pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming a hallmark of PDAC. Glucose glutamine metabolism are extensively rewired in order to fulfil both energetic synthetic demands this aggressive tumour maintain favorable redox homeostasis. The mitochondrial pyruvate carrier (MPC), (SLC1A5_Var), glutamate (GC), aspartate/glutamate (AGC), uncoupling protein 2 (UCP2) have all been shown influence PDAC cell growth progression. expression MPC downregulated its overexpression reduces rate, whereas other four transporters usually overexpressed loss one or more them renders cells unable grow proliferate by altering levels crucial metabolites such aspartate. aim review comprehensively evaluate current experimental evidence about function these carriers metabolic rewiring. Dissecting precise role context microenvironment necessary for targeted drug development.

Language: Английский

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The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease

Biomolecules, Journal Year: 2023, Volume and Issue: 13(2), P. 261 - 261

Published: Jan. 31, 2023

Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product glycolysis in the cytosol, it must be transported into mitochondrial matrix for energy stored this nutrient to fully harnessed generate ATP or become building block new biomolecules. Given requirement import, is not surprising that pyruvate carrier (MPC) has emerged as target therapeutic intervention variety diseases characterized by altered and In review, we focus on role MPC related pathways liver regulating hepatic systemic metabolism summarize current state targeting pathway treat liver. Available evidence suggests inhibiting hepatocytes other cells produces beneficial effects treating type 2 diabetes nonalcoholic steatohepatitis. We also highlight areas where our understanding incomplete regarding pleiotropic inhibition.

Language: Английский

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Warburg Effect Revisited: Embodiment of Classical Biochemistry and Organic Chemistry. Current State and Prospects

Biochemistry (Moscow), Journal Year: 2023, Volume and Issue: 88(S1), P. S1 - S20

Published: Jan. 1, 2023

Language: Английский

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