Acute promyelocytic leukemia (APL) is considered a distinct entity among the acute myeloid leukemias (AML). A series of carbazole derivatives were synthesized and examined for their growth inhibition effects on APL cell line HL-60. Cells treated with these compounds for 24 hours showed dose-dependent decrease of cell viability as determined by propidium iodide DNA staining method. The structure-activity relationships (SAR) in this series were also examined. We found compounds LCY-11, LCY-12, LCY-15 and LCY-16 had the highest growth inhibitory effect with IC50 7.29μM, 3.10μM, 8.20μM and 4.76μM respectively. By microscopical examination, DAPI staining and sub-G1 nuclear DNA analysis, after 24 hours treatment, these compounds induced significant cellular characteristics of apoptosis, including cell shrinking, chromatin condensation, fragmentation of nuclei, and formation of apoptotic bodies. DNA from HL-60 cells after 24h treatment displayed the characteristic internucleosomal ladder of DNA fragments. In addition, these compounds induced G2/M arrest by cell cycle analysis. Our findings indicate that the ability to achieve significant proliferation inhibition by LCY-11, 12, 15, 16 may be directly related to the induction of apoptosis and cell cycle arrest.
關聯:
The 16th Joint Annual Conference of Biomedical Sciences (2001)
