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Metabolically inducing defects in DNA repair sensitizes -wild-type cancer cells to replication stress.
Sci Signal
November 2024
Division of Cancer Biology, Cancer Institute of JFCR, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
Metabolic reprogramming from oxidative respiration to glycolysis is generally considered to be advantageous for tumor initiation and progression. However, we found that breast cancer cells forced to perform glycolysis acquired a vulnerability to PARP inhibitors. Small-molecule inhibition of mitochondrial respiration-using glyceollin I, metformin, or phenformin-induced overproduction of the oncometabolite lactate, which acidified the extracellular milieu and repressed the expression of homologous recombination (HR)-associated DNA repair genes.
View Article and Find Full Text PDFProgress in antitumor mechanisms and applications of phenformin (Review).
Oncol Rep
November 2024
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
Phenformin, a biguanide compound, has attracted increased attention due to its prominent antitumor activity. As a multi‑target agent, the antitumor effects of phenformin involve a wide range of factors, including inhibition of mitochondrial complex I, activation of AMP‑activated protein kinase, impact on the tumor microenvironment, suppression of cancer stem cells and others. In addition, phenformin has been shown to markedly augment the effectiveness of various clinical treatment methods, including radiotherapy, chemotherapy, targeted therapy and immunotherapy.
View Article and Find Full Text PDFTopical application of phenformin ameliorates the psoriasis-like inflammatory response via the inhibition of c-Myc expression in keratinocytes.
Biochem Biophys Res Commun
December 2024
Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Engineering Laboratory for Biomaterials and Tissue Regeneration, Ningbo Stomatology Hospital, Savaid Stomatology School, Hangzhou Medical College, Ningbo, Zhejiang, 315016, China. Electronic address:
Background: Psoriasis is a chronic inflammatory skin disease characterized by a complex pathogenesis involving various types of cells and cytokines. Among those, the pro-inflammatory cytokine IL-23/IL-17A axis plays a crucial role in the development and rapid progression of psoriasis. Phenformin, a derivative of metformin and a member of the biguanide class of drugs, exhibits superior anti-inflammatory and anti-tumor efficacy compared to metformin.
View Article and Find Full Text PDFAMP-dependent kinase stimulates the expression of αKlotho.
FEBS Open Bio
October 2024
Department of Physiology, University of Hohenheim, Stuttgart, Germany.
Renal αKlotho along with fibroblast growth factor 23 regulates phosphate and vitamin D metabolism. Its cleavage yields soluble Klotho controlling intracellular processes. αKlotho has anti-inflammatory and antioxidant effects and is nephro- and cardioprotective.
View Article and Find Full Text PDFSynthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer.
Eur J Med Chem
September 2024
Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma (PDAC). Despite some progress, current LDH inhibitors have poor structural and physicochemical properties or exhibit unfavorable pharmacokinetics that have hampered their development. The present study reports the synthesis and biological evaluation of a novel class of LDHA inhibitors comprising a succinic acid monoamide motif.
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