Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia.
OBJECTIVE
A high-rate glycolysis is a fundamental property of solid tumors and is associated with an over-expression of glucose transporters and glycolytic enzymes. We hypothesize that over-expression of glucose transporters in tumors prevents apoptosis, promotes cancer cell survival, and confers drug resistance. Inhibition of glucose transporter will preferentially sensitize the anticancer effects of chemotherapeutic drugs to overcome drug resistance in hypoxia.


METHODS
Glucose transporter expressions were detected in cancer tissues and NCI 60 cancer cells with immunostaining and DNA microarray. Glucose uptake was measured with 3H-2-deoxy-glucose. Cytotoxicity of daunorubicin (DNR) in combination of glucose inhibitor was detected by MTS assay under hypoxic condition. Early stage apoptosis was monitored with Annexin V-FITC staining.


RESULTS
Immunostaining showed that GLUT1 was significantly increased in hypoxic regions of the human colon and breast tumors. The expression profiles of all glucose transporters in NCI 60 cancer cells exhibited distinct expression patterns. Phloretin exhibited more than 60% glucose uptake inhibition. Hypoxia conferred two to fivefold higher drug resistance in SW620 and K562 to DNR. Inhibition of glucose uptake by phloretin sensitized cancer cells to DNR for its anticancer activity and apoptosis to overcome drug resistance only under hypoxia.


CONCLUSIONS
Cancer cells heavily rely on glucose transporters for glucose uptake to facilitate a high-rate glycolysis under hypoxia for their survival and drug resistance. Combination of glucose transporter inhibitors and chemotherapeutic drugs may provide a preferential novel therapeutic strategy to overcome drug resistance in hypoxia.
Cao
Xianhua
X
Division of Pharmaceutics, School of Pharmacy, The Ohio State University, 500 W. 12th Ave, Columbus, OH 43210, USA.
Fang
Lanyan
L
Gibbs
Seth
S
Huang
Ying
Y
Dai
Zunyan
Z
Wen
Ping
P
Zheng
Xincheng
X
Sadee
Wolfgang
W
Sun
Duxin
D
D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors*; D051272:Glucose Transporter Type 1 / Q000032:analysis; D051274:Glucose Transporter Type 3 / Q000032:analysis; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010693:Phloretin / Q000494:pharmacology*
D051246:Glucose Transport Proteins, Facilitative; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; C495677:SLC2A1 protein, human; C495687:SLC2A3 protein, human; D005947:Glucose; D010693:Phloretin; D003630:Daunorubicin