Echinomycin and a novel analogue induce apoptosis of HT-29 cells via the activation of MAP kinases pathway

Echinomycin, in typical DNA minor groove binder, had comparable efficacy compared to 5-FU in the phase II trail of colon cancer treatment. To improve echinomycin’s drawback (hydrophobicity, toxicity), we synthesized the YK-2000 series (echinomycin analogues). Among these, YK-2000 had the best in vit...

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Published in:Pharmacological research 2004-08, Vol.50 (2), p.201-207
Main Authors: Park, Ju Youn, Park, Su Jung, Shim, Kwang Yong, Lee, Kyu Jae, Kim, Yun-Bong, Kim, Yong Hae, Kim, Soo Kie
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Cytological Techniques
DNA Fragmentation - drug effects
Echinomycin
Echinomycin - analogs & derivatives
Echinomycin - chemistry
Echinomycin - pharmacology
Forecasting
Formazans
HT-291
HT29 Cells
Humans
Korea
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
MAP kinases
Mitogen-Activated Protein Kinase Kinases - drug effects
Mitogen-Activated Protein Kinase Kinases - physiology
Tetrazolium Salts
YK-2000
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Summary:Echinomycin, in typical DNA minor groove binder, had comparable efficacy compared to 5-FU in the phase II trail of colon cancer treatment. To improve echinomycin’s drawback (hydrophobicity, toxicity), we synthesized the YK-2000 series (echinomycin analogues). Among these, YK-2000 had the best in vitro cytotoxicity on six different human solid cancer cell lines. Echinomycin and YK-2000 were enabled to induce the apoptosis on the HT-29 colorectal cancer cell line. The hypothesis that apoptosis in the HT-29 cell was triggered by echinomycin and YK-2000 were supported through DNA laddering, poly-(ADP-ribose) polymerase (PARP) cleavage, and flow cytometric analysis. In order to explore the signaling pathway of echinomycin and YK-2000, we examined the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 MAP kinase. However, what the mechanism of cancer cell death would be induced by echinomycin and YK-2000 is unknown. Here, we present some evidence that one of the major apoptotic signaling pathways induced by echinomycin and YK-2000 is possibly the MAP kinases pathway in HT-29 human colon cancer cells.
ISSN:1043-6618
1096-1186
DOI:10.1016/j.phrs.2004.01.005