RARalpha is a regulatory factor for Am-80-induced cell growth inhibition of hematologic malignant cells.

Abstract

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.

• Authors: Shiro Jimi, Kota Mashima, Taichi Matsumoto, Shuji Hara, Junji Suzumiya, Kazuo Tamura
• Journal: International journal of oncology (Int J Oncol) Vol. 31 Issue 2 Pg. 397-404 (Aug 2007) ISSN: 1019-6439 [Print] Greece
• PMID: 17611697 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• RARA protein, human
• Receptors, Retinoic Acid
• Retinoic Acid Receptor alpha
• Retinoids
• Tetrahydronaphthalenes
• Transforming Growth Factor beta2
• tamibarotene

Topics

• Apoptosis
• Benzoates (pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Dose-Response Relationship, Drug
• Genes, Tumor Suppressor
• HL-60 Cells
• Hematologic Neoplasms (drug therapy)
• Humans
• K562 Cells
• Phosphorylation
• Receptors, Retinoic Acid (physiology)
• Retinoic Acid Receptor alpha
• Retinoids (pharmacology)
• Tetrahydronaphthalenes (pharmacology)
• Transforming Growth Factor beta2 (metabolism)