Induction of G2/M phase arrest and apoptosis by a novel enediyne derivative, THDB, in chronic myeloid leukemia (HL-60) cells.

Abstract

(Z)-2-(6-(Thieanisyl-2-yl)hexa-3-en-1,5-diynyl)benzenamine (THDB), an enediyne compound, was identified in our laboratory as a novel antineoplastic agent with broad spectrum of antitumor activities against many human cancer cells. THDB was found to inhibit the growth of HL-60 cells in a time-and dose-dependent manner. Cell cycle analysis showed G2/M phase arrest in HL-60 cells following 48 h exposure to THDB. Analysis of the cell cycle regulatory proteins demonstrated that THDB did not change the steady-state levels of cyclin B1, cyclin E, Cdk1 and Cdc25C, but decreased the protein levels of Cdk2 and cyclin A. THDB also caused a marked increase in apoptosis, as characterized by DNA fragmentation (DNA ladder and sub G1 formation), and poly (ADP-ribose) polymerase (PARP) cleavage, which was associated with activation of caspase-3, caspase-8 and caspase-9. Moreover, the THDB-induced apoptosis was significantly attenuated in the presence of specific inhibitors of caspase-3, -8 and -9. These molecular alterations provide an insight into THDB-caused growth inhibition, G2/M arrest and apoptotic death of HL-60 cells.

• Authors: Yu-Jhang Lu, Sheng-Huei Yang, Ching-Ming Chien, Yi-Hsiung Lin, Xiu-Wei Hu, Zchong-Zcho Wu, Ming-Jung Wu, Shinne-Ren Lin
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 21 Issue 1 Pg. 90-8 (Feb 2007) ISSN: 0887-2333 [Print] England
• PMID: 17064874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (Z)-2-(6-(thieanisyl-2-yl)hexa-3-en-1,5-diynyl)benzenamine
• Actins
• Antineoplastic Agents
• Enediynes
• Tetrazolium Salts
• Thiazoles
• Poly(ADP-ribose) Polymerases
• Caspases
• thiazolyl blue

Topics

• Actins (biosynthesis)
• Antineoplastic Agents (chemical synthesis, toxicity)
• Apoptosis (drug effects)
• Blotting, Western
• Caspases (biosynthesis)
• Cell Division (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Enediynes (chemical synthesis, toxicity)
• Flow Cytometry
• G1 Phase (drug effects)
• G2 Phase (drug effects)
• HL-60 Cells
• Humans
• Poly(ADP-ribose) Polymerases (biosynthesis)
• Resting Phase, Cell Cycle (drug effects)
• Tetrazolium Salts
• Thiazoles