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In vitro Cytotoxicity and Apoptotic Effect of Chloromethyl-2-dihydroxyphosphinyl-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline on HL-60 Cells  

Kim, Kun-Jung (Department of Pathology, College of Oriental Medicine, Wonkwang University)
Ju, Sung-Min (Department of Pathology, College of Oriental Medicine, Wonkwang University)
Kim, Myung-Wan (Department of Pathology, College of Oriental Medicine, Wonkwang University)
Lee, Chai-Ho (Division of Natural Science and Technology, College of Natural Sciences, Wonkwang University)
Kim, Won-Sin (Division of Natural Science and Technology, College of Natural Sciences, Wonkwang University)
Yun, Young-Gab (Department of Prescription, College of Oriental Medicine, Wonkwang University)
Yun, Yoo-Sik (Korea Institute of Oriental Medicine)
Jeon, Byung-Hun (Department of Pathology, College of Oriental Medicine, Wonkwang University)
Publication Information
Journal of Physiology & Pathology in Korean Medicine / v.19, no.3, 2005 , pp. 772-778 More about this Journal
Abstract
The chloromethyl-2-dihydroxyphosphinyl-6,7-dimethoxy-1,2,3,4-tetrahydro- isoquinoline (CDDT) is a newly synthesized derivative from 1,2,3,4-Tetra- hydroisoquinoline (THIQ). The THIQs include potent cytotoxic agents that display a range of antitumor activities, antimicrobial activity, and other biological properties. In this study, we investigated the effect of CDDT on the cytotoxicity, induction of apoptosis in human promyelocytic leukemia cells (HL-60 cells). CDDT showed a significant cytotoxic activity in HL-60 cells ($IC_{50}$ = approximately $37\;{\mu}g/ml$) at a 24 hr incubation. Treatment of HL-60 cells with CDDT displayed several features of apoptosis, including formation of DNA ladders in agarose gel electrophoresis, morphological changes of HL-60 cells with DAPI stain. Here we observed that CDDT caused activation of caspase-3, caspase-8, and caspase-9. The most efficacious time on the activation of caspases-3 was achieved at 12 hr. Further molecular analysis demonstrated that CDDT led to cleavage of poly(ADP-ribose) polymerase (PARP), increase of hypodiploid (Sub-G1) population in the flow cytometric analysis. In conclusion, these above results indicate that CDDT dramatically suppresses HL-60 cell growth by activation of caspase-3 with caspase-8, -9 activity. These data may support a pivotal mechanism for the use of CDDT in the prevention and treatment of leukemia.
Keywords
Apoptosis; CDDT; caspase-8; caspase-9; caspase-3;
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