Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer.
Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of (18)F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters. The profound energetic imbalance activates phosphorylation and is subsequently followed by cell death. More importantly, the "in vivo" relevance of this effect is confirmed by studies of orthotopic xenografts of MDA-MB-231 cells in athymic (nu/nu) mice. Administration of high drug doses after tumor development caused an evident tumor necrosis in a time as short as 48 h. On the other hand, 1 mo metformin treatment markedly reduced cancer glucose consumption and growth. Taken together, our results strongly suggest that HK inhibition contributes to metformin therapeutic and preventive potential in breast cancer.
CNR Institute of Bioimages and Molecular Physiology; Milan, Section of Genoa, Genoa, Italy.
Cecilia
C
Marini
Barbara
B
Salani
Michela
M
Massollo
Adriana
A
Amaro
Alessia Isabella
AI
Esposito
Anna Maria
AM
Orengo
Selene
S
Capitanio
Laura
L
Emionite
Mattia
M
Riondato
Gianluca
G
Bottoni
Cinzia
C
Massara
Simona
S
Boccardo
Marina
M
Fabbi
Cristina
C
Campi
Silvia
S
Ravera
Giovanna
G
Angelini
Silvia
S
Morbelli
Michele
M
Cilli
Renzo
R
Cordera
Mauro
M
Truini
Davide
D
Maggi
Ulrich
U
Pfeffer
Gianmario
G
Sambuceti
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005947:Glucose / Q000378:metabolism*; D064593:Heterografts; D006593:Hexokinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
D000970:Antineoplastic Agents; D008687:Metformin; D006593:Hexokinase; D005947:Glucose
breast cancer; glucose metabolism; hexokinases; in vivo imaging; metformin; orthotopic xenografts