Salicylketoximes That Target Glucose Transporter 1 Restrict Energy Supply to Lung Cancer Cells.
The glucose transporter GLUT1 is frequently overexpressed in most tumor tissues because rapidly proliferating cancer cells rely primarily on glycolysis, a low-efficiency metabolic pathway that necessitates a very high rate of glucose consumption. Because blocking GLUT1 is a promising anticancer strategy, we developed a novel class of GLUT1 inhibitors based on the 4-aryl-substituted salicylketoxime scaffold. Some of these compounds are efficient inhibitors of glucose uptake in lung cancer cells and have a notable antiproliferative effect. In contrast to their 5-aryl-substituted regioisomers, the newly synthesized compounds reported herein do not display significant binding to the estrogen receptors. The inhibition of glucose uptake in cancer cells by these compounds was further observed by fluorescence microscopy imaging using a fluorescent analogue of glucose. Therefore, blocking the ability of tumor cells to take up glucose by means of these small molecules, or by further optimized derivatives, may be a successful approach in the development of novel anticancer drugs.
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy.
Carlotta
C
Granchi
Edison Biotechnology Institute, Ohio University, the Ridges, Athens, OH, 45701, USA.
Yanrong
Y
Qian
Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL, 61801, USA.
Hyang Yeon
HY
Lee
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy.
Ilaria
I
Paterni
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy.
Carolina
C
Pasero
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy.
Jessica
J
Iegre
Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL, 61801, USA.
Kathryn E
KE
Carlson
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy.
Tiziano
T
Tuccinardi
Edison Biotechnology Institute, Ohio University, the Ridges, Athens, OH, 45701, USA.
Xiaozhuo
X
Chen
Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL, 61801, USA.
John A
JA
Katzenellenbogen
Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL, 61801, USA.
Paul J
PJ
Hergenrother
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy. filippo.minutolo@farm.unipi.it.
Filippo
F
Minutolo
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004734:Energy Metabolism / Q000187:drug effects*; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; D010091:Oximes; C495677:SLC2A1 protein, human
GLUT1; Warburg effect; cancer metabolism; glycolysis; oximes