Inhibitors of glucose transport and glycolysis as novel anticancer therapeutics

Table 1 Glycolytic inhibitors and modulators

Compound name	Target protein	Status	Ref.
2-DG	Inhibits HK	Phase I-completed (Jul 2008) Phase I/II-terminated (Mar 2011)	NCT00096707 NCT00633087
3-BP	Inhibits HK	Pre-clinical	[66-74]
Lonidamine	Inhibits mitochondrial HK2	Phase II/III-terminated (Aug/Dec 2006)	NCT00237536 NCT00435448
3PO	Inhibits PFK2	Pre-clinical	[90]
N4A, YZ9	Inhibits PFK2	Pre-clinical	[91]
PGMI-004A	Inhibits PGAM1	Pre-clinical	[96]
MJE3	Inhibits PGAM1	Pre-clinical	[98]
TT-232	Inhibits PKM2	Phase II-completed (Mar 2008) Phase II-terminated (Oct 2010)	NCT00422786 NCT00735332
Shikonin/alkannin	Inhibits PKM2	Pre-clinical	[108]
ML265 (TEPP-46)	Activates PKM2	Pre-clinical	[116,117]
FX11	Inhibits LDHA	Pre-clinical	[126]
Quinoline 3-sulfonamides	Inhibit LDHA	Pre-clinical	[141]
DCA	Inhibits PDK	Phase I-ongoing Phase I-ongoing Phase II-completed (Aug 2009)	NCT00566410 NCT01111097 NCT00540176
6-AN	Inhibits G6PD	Pre-clinical	[159-161]
Oxythiamine	Inhibits TKTL1	Pre-clinical	[170-173]

2-DG: 2-deoxyglucose; 3-BP: 3-bromopyruvate; DCA: Dichloroacetate; 6-AN: 6-aminonicotinamide; HK: Hexokinase; PFK: Phosphofructokinase; PGAM: Phosphoglycerate mutase; PKM2: Pyruvate kinase M2; LDH: Lactate dehydrogenase; PDK: Pyruvate dehydrogenase kinase; G6PD: Glucose-6-phosphate dehydrogenase; TKTL1: Transketolase-like enzyme 1.

Table 2 Expression of glucose transporters and their major characteristics

Protein	Class	Expression	Affinity to glucose	Major features	Expression in cancer
GLUT1	I	Ubiquitous (abundant in brain and erythrocytes)[207]	High[201,208,211]	Constitutive basal glucose uptake[207]	Over-expressed[176,203]
GLUT2	I	Liver, retina, pancreatic islet cells[176,198]	Low[201,211]	Glucose sensing, fructose transport[176,200]	Abnormal[176,202-204]
GLUT3	I	Brain[196]	High[201,211]	Supplements GLUT1 in brain[176,196]	Over-expressed[176,205]
GLUT4	I	Muscle, fat, heart[210]	High[208,209,211]	Insulin responsive[210]	Abnormal[188]
GLUT5	II	Intestine, testis, kidney, erythrocytes[213,214]	Very low[212]	Fructose transport[212]	Abnormal[176,203]
GLUT6	III	Spleen, leukocytes, brain[215]	Low[215]	Sub-cellular redistribution[216]	UD[203]
GLUT7	II	Liver, intestine, colon, testis, prostate[216,217]	High[217]	Glucose and fructose transport[217]	ND
GLUT8	III	Testis, brain[219]	High[219]	Sub-cellular redistribution, multisubstrates[216]	Over-expressed[218]
GLUT9	II	Liver, kidney, pancreatic cells[220,222]	High[221]	Multisubstrates[216]	UD[203]
GLUT10	III	Liver, pancreas[223]	High[224]	Glucose transport[224]	ND
GLUT11	II	Heart, muscle[225]	Low[225]	Inhibited by fructose[225]	ND
GLUT12	III	Heart, prostate, muscle, fat, intestine[226]	High[227]	Insulin-reponsive[226]	Abnormal[206]
HMIT	III	Brain[228]	No	H+/myo-inositol transport[228]	ND
GLUT14	I	Testis[229]	ND	ND	ND

GLUTs: Glucose transporters; HMIT: H⁺/myo-inositol transporter; ND: Not determined; UD: Undetectable.

Table 3 Inhibitors of glucose transporters 1, glucose transporters 2, glucose transporters 3 and glucose transporters 4

Inhibitor	Target GLUT	Status	Ref.
WZB117	GLUT1	Animal study	Liu et al[28], 2012
STF-31	GLUT1	Animal study	Chan et al[240], 2011
Fasentin	GLUT1	In vitro	Wood et al[242], 2008
Apigenin	GLUT1	Phase II	NCT00609310
Genistein	GLUT1	Phase II/III	NCT00118040; NCT00584532
Oxime-based GLUT1 inhibitors	GLUT1	Animal study	Tuccinardi et al[255], 2013
Pyrrolidinone derived GLUT1 inhibitors	GLUT1	In vitro	Ulanovskaya et al[257], 2011
Phloretin	GLUT2	Animal study	Wu et al[258], 2009
Quercetin	GLUT2	Phase I	NCT01912820
DNA-damaging anticancer agents	GLUT3	In vitro	Watanabe et al[269], 2010
GSK-3 inhibitors	GLUT3	In vitro	Watanabe et al[270], 2012
Ritonavir	GLUT4	Phase I/II	NCT01009437; NCT01095094
Silibinin	GLUT4	Phase I/II	Flaig et al[280], 2007; NCT00487721

GLUTs: Glucose transporters.