Suppression of P-glycoprotein expression by antipsychotics trifluoperazine in adriamycin-resistant L1210 mouse leukemia cells.
Multidrug resistance (MDR) to unrelated chemotherapeutic drugs can be mediated by overexpression of P-glycoprotein (P-gp), the mdr gene product. Trifluoperazine (TFP), a phenothiazine derivative antipsychotics, is known to reverse MDR of tumor cell lines by blocking P-gp efflux function. In the present study, we evaluated the effect of TFP on the expression of P-gp in multidrug-resistant L1210/Adr mouse leukemic cell lines, which are characterized by overexpession of P-gp. We found that TFP induced the downregulation of P-gp protein and mdr1b mRNA in a dose- and time-dependent manner in L1210/Adr cells. TFP reduction of mdr1b mRNA was paralleled by transcriptional suppression of the mdr1b promoter. Moreover, TFP restored the adriamycin-induced apoptosis in L1210/Adr cells. These results suggest that TFP may have utility as an adjuvant in the therapy of leukemia for the reversal of P-gp-dependent MDR as well as for the management of psychological symptoms in the cancer patients.
Shin
Soon Young
SY
Division of Molecular and Life Science, Department of Bio-Nano Technology, College of Science and Technology, Hanyang University, Ansan 426-791, Republic of Korea.
Choi
Byeong Hyeok
BH
Kim
Jae-Ryong
JR
Kim
Jung-Hye
JH
Lee
Young Han
YH
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014268:Trifluoperazine / Q000494:pharmacology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D014150:Antipsychotic Agents; D004317:Doxorubicin; D016328:NF-kappa B; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D012333:RNA, Messenger; D014268:Trifluoperazine; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C499321:Parp1 protein, mouse