title: Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A (LDH-A) as starvation agents against cancer cells.
abstract: Highly invasive tumor cells are characterized by a metabolic switch, known as the Warburg effect, from "normal" oxidative phosphorylation to increased glycolysis even under sufficiently oxygenated conditions. This dependence on glycolysis also confers a growth advantage to cells present in hypoxic regions of the tumor. One of the key enzymes involved in glycolysis, the muscle isoform of lactate dehydrogenase (LDH-A), is overexpressed by metastatic cancer cells and is linked to the vitality of tumors in hypoxia. This enzyme may be considered as a potential target for new anticancer agents, since its inhibition cuts cancer energetic and anabolic supply, thus reducing the metastatic and invasive potential of cancer cells. We have discovered new and efficient N-hydroxyindole-based inhibitors of LDH-A, which are isoform-selective (over LDH-B) and competitive with both the substrate (pyruvate) and the cofactor (NADH). The antiproliferative activity of these compounds was confirmed on a series of cancer cell lines, and they proved to be particularly effective under hypoxic conditions. Moreover, NMR experiments showed that these compounds are able to reduce the glucose-to-lactate conversion inside the cell.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Granchi
authors.forename: Sarabindu
authors.initials: S
authors.lastname: Roy
authors.forename: Chiara
authors.initials: C
authors.lastname: Giacomelli
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Mario
authors.initials: M
authors.lastname: Lanza
authors.forename: Laura
authors.initials: L
authors.lastname: Betti
authors.forename: Gino
authors.initials: G
authors.lastname: Giannaccini
authors.forename: Antonio
authors.initials: A
authors.lastname: Lucacchini
authors.forename: Nicola
authors.initials: N
authors.lastname: Funel
authors.forename: Leticia G
authors.initials: LG
authors.lastname: León
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.forename: Rahul
authors.initials: R
authors.lastname: Palchaudhuri
authors.forename: Emilia C
authors.initials: EC
authors.lastname: Calvaresi
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000378:metabolism; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D007527:Isoenzymes; D009243:NAD; D019344:Lactic Acid; D019289:Pyruvic Acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D005947:Glucose