Cyclin-dependent kinase inhibitor SU9516 enhances sensitivity to methotrexate in human T-cell leukemia Jurkat cells.
Methotrexate (MTX) has been used to treat various hematological malignancies. Since MTX prevents tumor cells from proliferating by inhibiting dihydrofolate reductase (DHFR), DHFR expression is a key determinant of resistance to MTX in malignant hematological tumor cells. The antiproliferative effect of MTX was significantly enhanced by the knockdown of DHFR expression by siRNA in Jurkat cells. Therefore, a novel strategy down-regulating DHFR expression seems promising for enhancing sensitivity to MTX. We found that SU9516, a cyclin-dependent kinase inhibitor, reduced the expression of both DHFR mRNA and protein. Moreover, we found that DHFR promoter activity was attenuated by SU9516 dependent on the E2F site. Finally, pretreatment with SU9516 significantly enhanced sensitivity to MTX in a colony formation assay. We conclude that a combination of cyclin-dependent kinase inhibitors and MTX may be useful for overcoming resistance to MTX.
Uchiyama
Hitoji
H
Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Sowa
Yoshihiro
Y
Wakada
Miki
M
Yogosawa
Mayumi
M
Nakanishi
Ryoko
R
Horinaka
Mano
M
Shimazaki
Chihiro
C
Taniwaki
Masafumi
M
Sakai
Toshiyuki
T
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D019169:Jurkat Cells; D008727:Methotrexate / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
C471843:6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine; D000964:Antimetabolites, Antineoplastic; D007093:Imidazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011687:Purines; C433985:SU 9516; D013762:Tetrahydrofolate Dehydrogenase; D018844:Cyclin-Dependent Kinases; D008727:Methotrexate