Energy metabolism of human LoVo colon carcinoma cells: correlation to drug resistance and influence of lonidamine.
The relationship between modification of energy metabolism and extent of drug resistance was investigated in two sublines (LoVoDX and LoVoDX10) from human LoVo colon carcinoma cells that exhibit different degrees of resistance to doxorubicin. Results indicated that the extent of alteration in energy metabolism strictly correlated with degree of resistance. In LoVoDX cells, only 14CO2 production was enhanced, whereas in the more resistant LoVoDX10 cells, both 14CO2 and aerobic lactate production were stimulated. The basal and glucose-supported efflux rate and the amount of drug extruded by LoVoDX10 cells were significantly higher than in the resistant LoVoDX cells. Because the expression of surface P-170 glycoprotein was similar in both cell lines, this phenomenon was attributed to increased efflux pump activity resulting from greater ATP availability. Inhibition of 14CO2 production, aerobic glycolysis, and clonogenic activity by lonidamine (LND) increased with enhancement of the energy metabolism. Moreover, LND, by affecting energy-yielding processes, reduced intracellular ATP content, lowered the energy supply to the ATP-driven efflux pump, and inhibited, almost completely, doxorubicin extrusion by resistant LoVo cells. These findings strongly suggest that LND, currently used in tumor therapy, reduces drug resistance by restoring the capacity to accumulate and retain drug of cells with the MDR phenotype that overexpress P-170.
Fanciulli
M
M
Center for Experimental Research, Regina Elena Cancer Institute, Rome, Italy.
Bruno
T
T
Giovannelli
A
A
Gentile
F P
FP
Di Padova
M
M
Rubiu
O
O
Floridi
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002245:Carbon Dioxide / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D007700:Kinetics; D019344:Lactic Acid / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D007191:Indazoles; D002245:Carbon Dioxide; D019344:Lactic Acid; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D007521:Isocitrate Dehydrogenase; D002950:Citrate (si)-Synthase; D006593:Hexokinase; D005947:Glucose; C016371:lonidamine