Multidrug resistance P-glycoprotein function of bone marrow hematopoietic cells and the reversal agent effect.
The multidrug resistance P-glycoprotein (P-gp) expression and function in hematopoietic stem/progenitor cells were studied to investigate whether the inhibition of hematopoietic cell P-gp function by multidrug resistance reversal agent increases the cytotoxicity of chemotherapy drugs on the hematopoietic cells. The expression of P-gp on the surface of CD34+ cells from healthy human marrow was examined by flow cytometry. The multidrug resistance reversal agent MS-209 was used to measure the effects of MS-209 on the Rhodamin-123 uptaking of CD34+ hematopoietic cells. By using methylcellulose semi-solid culture, normal human granulocyte-macrophage clonal formation unit (CFU-GM) was cultured. The changes in CFU-GM inhibitory rate caused by daunorubicin were determined in the presence or absence of MS-209. The results showed that the P-gp expression rate of bone marrow CD34+ cells was 13.3%. MS-209 obviously increased the Rhodamin-123 uptake of CD34+ positive cells. The mean inhibitory rate of daunorubicin for CFU-GM was 29.6%, but it was increased to 43.3% in the presence of MS-209 with the difference being significant (P < 0.05). It was concluded that hematopoietic cells expressed P-gp protein and possessed active function. MS-209 could inhibit the membrane efflux pump and increase the cytotoxicity of chemotherapy drugs to the clonal growth of hematopoetic stem cells, suggesting the side effects of these drugs on the hematopoietic system should be taken into consideration in the clinical use.
Chen
Z
Z
Institute of Hematology, Tongji Medical University, Wuhan 430022.
Takeshita
A
A
Zou
P
P
Liu
Z
Z
Kozaka
M
M
You
Y
Y
Song
S
S
Ohnishi
K
K
Ohno
R
R
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D011804:Quinolines / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D011804:Quinolines; C087719:dofequidar; D003630:Daunorubicin