Inhibition of HIV-1 Tat-mediated transactivation by quinacrine and chloroquine.
The replication of human immunodeficiency virus type 1 (HIV-1) requires cellular components to interact with regulatory elements located in the long terminal repeat (LTR) as well as viral proteins Tat and Rev. Several well known signaling transduction inhibitors were tested to determine their effects on the Tat-mediated transactivation using a transfection assay with the bacterial chloramphenicol acetyltransferase gene under the control of the HIV-1 LTR. The protein kinase C inhibitors curcumin and staurosporine, but not a tyrosine kinase inhibitor herbimycine A, inhibited Tat-mediated LTR-driven transactivation. Two antimalarial drugs quinacrine and chloroquine, that are also arachidonic acid metabolism inhibitors, were found to inhibit the Tat-mediated LTR-driven gene expression. Another inhibitor of arachidonic acid metabolism 4-bromophenacyl bromide was also found to inhibit Tat-mediated gene expression driven by HIV-1 LTR. However, the antimalarial drug quinine elicited no effects on Tat-mediated transactivation. These results suggest that the anti-arachidonic acid metabolism properties of quinacrine and chloroquine may be responsible for their ability to inhibit Tat-mediated LTR-regulated gene expression.
Jiang
M C
MC
Institute of Biochemistry, School of Medicine, National Taiwan University, Taipei, Republic of China.
Lin
J K
JK
Chen
S S
SS
D000098:Acetophenones / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology*; D016227:Benzoquinones; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015696:Gene Products, tat / Q000378:metabolism*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D047029:Lactams, Macrocyclic; D011796:Quinacrine / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D019311:Staurosporine; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
D000098:Acetophenones; D000470:Alkaloids; D000962:Antimalarials; D016227:Benzoquinones; D015696:Gene Products, tat; D047029:Lactams, Macrocyclic; D011809:Quinones; D054322:tat Gene Products, Human Immunodeficiency Virus; D017828:Rifabutin; C020754:herbimycin; D002738:Chloroquine; D011796:Quinacrine; D019311:Staurosporine; D003474:Curcumin; C006821:4-bromophenacyl bromide