Study of sodium orthovanadate as a reverser of multidrug resistance on lymphoblastic leukemic CEM/VLB100 cells.
The occurrence of multidrug resistance (MDR) is the major cause of failure of cancer chemotherapy. Finding a way to circumvent this problem is now a major challenge in oncology. Multidrug resistant CEM/VLB100 cells accumulate 10 times less vinblastine (VLB) after 30 min than their sensitive counterparts (CEM cells). At a non-cytotoxic concentration (1 mM) of sodium orthovanadate (OVN), uptake by CEM/VLB100 cells was increased 4 times while no effect was observed on CEM cells. The action on VLB uptake of OVN and verapamil (VPL), an usual MDR modulator, was additive. In CEM/VLB100 cells, OVN did not alter efflux. Its cellular mechanism of action could involve a transitory stimulation of VLB influx (x3). OVN uptake in CEM and CEM/VLB100 cells was not significantly different and reached saturation after 30 s (180 pmol/10(6) CEM cells and 150 pmol/10(6) CEM/VLB100 cells). This OVN uptake was concentration dependent. IC50 of VLB and doxorubicin were decreased by approximately 43 and 62% after 1 hour's exposure to OVN and 48 hours of culture. Under these conditions, OVN was more efficient than OVN.
Colin
M
M
GIBSA, Laboratoire de Biochimie, UFR de Pharmacie, Reims, France.
Madoulet
C
C
Baccard
N
N
Arsac
F
F
Jardillier
J C
JC
D004317:Doxorubicin / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000503:physiopathology; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000627:therapeutic use*; D014700:Verapamil / Q000627:therapeutic use; D014747:Vinblastine / Q000627:therapeutic use
D014638:Vanadates; D014747:Vinblastine; D004317:Doxorubicin; D014700:Verapamil