TY - JOUR
T1 - Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A (LDH-A) as starvation agents against cancer cells
AU - Granchi, Carlotta
AU - Roy, Sarabindu
AU - Giacomelli, Chiara
AU - MacChia, Marco
AU - Tuccinardi, Tiziano
AU - Martinelli, Adriano
AU - Lanza, Mario
AU - Betti, Laura
AU - Giannaccini, Gino
AU - Lucacchini, Antonio
AU - Funel, Nicola
AU - León, Leticia G.
AU - Giovannetti, Elisa
AU - Peters, Godefridus J.
AU - Palchaudhuri, Rahul
AU - Calvaresi, Emilia C.
AU - Hergenrother, Paul J.
AU - Minutolo, Filippo
PY - 2011/3/24
Y1 - 2011/3/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79952806402&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79952806402&partnerID=8YFLogxK
U2 - 10.1021/jm101007q
DO - 10.1021/jm101007q
M3 - Article
C2 - 21332213
AN - SCOPUS:79952806402
SN - 0022-2623
VL - 54
SP - 1599
EP - 1612
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 6
ER -