RARalpha is a regulatory factor for Am-80-induced cell growth inhibition of hematologic malignant cells.
Retinoids are used for treatment of acute promyelocytic leukemia (APL). Am-80, Tamibarotene, binds to retinoic acid receptor alpha (RARalpha) more specifically than all-trans retinoic acid. We studied the tumor cell suppressive effects of Am-80, with respect to cytotoxicity and growth inhibition using eight myeloid and lymphoid malignant cells in culture (HL-60, HL-60R, K-562, Kasumi-1, MEG01, Raji, U266B1, and U937). The effects of Am-80 were examined during 9 days of incubation with 10(-7)-10(-5) M of Am-80 in culture medium, which was changed every 3 days. HL-60 were the only cells sensitive to Am-80-induced cytotoxicity; the latter reached more than 95% after 9 days of incubation, and death was primarily through apoptosis. The total mass of RARalpha in HL-60 was significantly greater (p<0.006) than in ATRA-resistant HL-60 (HL-60R) as well as all of other cells tested. However, in all cells excluding HL-60, Am-80 induced time- and dose-dependent cell growth inhibition without noticeable cytotoxicity. TGF-beta2 was released into the media containing cells incubated with Am-80 for 3 days. A dose-dependent increment of phosphorylation of Smad-2 was also detected. The relative amount of secreted TGF-beta2 correlated with the growth inhibition rates in all cells tested excluding HL-60, and with the total mass of RARalpha in the cells (p=0.0137). Our results indicate that Am-80-induced cell-type non-specific growth inhibition is mediated by TGF-beta2, where the total mass of RARalpha could be an important regulatory factor in hematologic malignant cells.
Jimi
Shiro
S
Central Laboratory of Pathology and Morphology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan. sjimi@fukuoka-u.ac.jp
Mashima
Kota
K
Matsumoto
Taichi
T
Hara
Shuji
S
Suzumiya
Junji
J
Tamura
Kazuo
K
D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D016147:Genes, Tumor Suppressor; D018922:HL-60 Cells; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D020014:K562 Cells; D010766:Phosphorylation; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*
D001565:Benzoates; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D053781:Transforming Growth Factor beta2; C061133:tamibarotene