Cyclosporin A inhibits HTLV-I tax expression and shows anti-tumor effects in combination with VP-16.
Adult T cell leukemia (ATL) is one of the most refractory malignant hematological diseases. Our previous studies demonstrated HTLV-1Tax protein involvement in clinical manifestation of the aggressive type of ATL and suggested the potential application of agents to inhibit Tax expression for ATL treatment. In the present study, we first examined Tax involvement in the resistance to VP-16-induced apoptosis using four HTLV-1 infected T cell clones and cTax DNA-transfected cells. Next, we examined whether cyclosporin A reduced expression of Tax and its related transfer factors on Western blot and CAT assay. We further investigated whether cyclosporin A in combination with VP-16 can induce apoptosis in HTLV-1 infected T cells. Tax-producing T cells, K3T and F6T, were resistant to VP-16 induced growth inhibition compared with that of the nonproducing cells, S1T and Su9T01. Experiments using S1T and Tax-expressing cDNA-transfected S1T demonstrated Tax-induced resistance to VP-16 induction of apoptosis by DNA ladder formation. Cyclosporin A reduced Tax expression in K3T by Western blot analysis and on CAT assay, showing maximal reduction of 61% and 60% compared to control culture using LTR CAT transfected Jurkat cells and K3T cells, respectively. Cyclosporin A also reduced the nuclear expression of two Tax-related transfer factors, ATF-1 and ATF-2 on Western blot. Cyclosporin A alone did not show any cytotoxicity by itself, but sensitized cells to VP-16 when combined with VP-16. Cyclosporin A may be a useful anti-ATL agent when combined with other anti-cancer agents possibly related to Tax inhibition.
Ozaki
Atsuo
A
Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
Arima
Naomichi
N
Matsushita
Kakushi
K
Uozumi
Kimiharu
K
Akimoto
Masaki
M
Hamada
Heiichiro
H
Kawada
Hideaki
H
Horai
Sawako
S
Tanaka
Yuetsu
Y
Tei
Chuwa
C
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016356:Gene Products, tax / Q000235:genetics* / Q000378:metabolism; D017405:Herpes Simplex Virus Protein Vmw65 / Q000494:pharmacology*; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans
D000970:Antineoplastic Agents; D016356:Gene Products, tax; D017405:Herpes Simplex Virus Protein Vmw65; C514970:tax protein, Human T-lymphotrophic virus 1; D005047:Etoposide; D016572:Cyclosporine