- 作者: In-Kyng Kim ; Chou-Chi H. Li ; Howard A. Young ; Jeong-Hwa Lee ; Ho-Shik Kim ; K. Pardhasaradhi ; Gregory E. Garcia ; Peter K. Chiang
- 作者服務機構: a Department of Biochemistry, Catholic University Medical College, Seoul, Korea;; b Intramural Research Support Program and; c Laboratory of Experimental Immunology, NCI-Frederick Cancer Research and Development Center, Frederick, Md., and; d Walter Reed Army Institute of Research, Washington, D.C., USA
- 中文摘要: --
- 英文摘要: A new class of potent apogens (apoptosis-inducing agents) has been identified, consisting of 3-deazaadenosine (DZA), 3-deaza-( ± )aristeromycin (DZAri) and l-β-D-arabinofuranosyl-lH-imidazo[4,5-c]pyridine (ara-3-deazaadenine; DZAra-A). They are inhibitors of S-adenosylhomocysteine hydrolase and indirect inhibitors of methylation. Furthermore, they have also been found to form 3-deaza-nucleotide analogs. The DZA analogs, DZA, DZAri, and DZAra-A, induced DNA fragmentation in a dose- and time-dependent manner, reaching a maximum at 250 μM after 72 h. Cycloheximide at 0.5 μg/ml completely blocked the DNA fragmentation induced by 250 μM of each of the analogs. Interestingly, exogenous 100 μM L-homocysteine thiolactone abrogated the DNA fragmentation caused by DZAri and DZAra-A, but not by DZA. Flow cytometric analysis showed that DZA arrested the cells in the G2/ M phase, whereas the S phase was arrested by DZAri. Correlated with the effect of DZA was a rapid decrease in the expression of c-myc, whereas nur77 and GAPDH were unaffected. In comparison, there was an elevated expression of IFN-γ mRNA without apparent change in bax, p53 or GAPDH mRNA after 24 h. After treatment with DZA, there was an elevated expression of NF-κB DNA binding activity, which became more pronounced at 24 h. Simultaneously, there was an apparent disappearance of AP-1 activity. Thus, DZA most likely inhibited the RNA synthesis of c-myc, a reduction of which could trigger a cascade of gene transcription leading to apoptosis in L1210 cells.
- 中文關鍵字: --
- 英文關鍵字: Apoptosis ; Cell cycle; 3-Deazaadenosine analogs ; L1210 lymphocytic leukemia cells ; c-myc; NF-kappa B