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 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.
Park
Ju Youn
JY
Department of Microbiology, Wonju College of Medicine, Yonsei University, Wonju 220-701, South Korea.
Park
Su Jung
SJ
Shim
Kwang Yong
KY
Lee
Kyu Jae
KJ
Kim
Yun-Bong
YB
Kim
Yong Hae
YH
Kim
Soo Kie
SK
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003584:Cytological Techniques; D053938:DNA Fragmentation / Q000187:drug effects; D004448:Echinomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D005544:Forecasting; D005562:Formazans; D019073:HT29 Cells; D006801:Humans; D007723:Korea; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000502:physiology*; D013778:Tetrazolium Salts
D000970:Antineoplastic Agents; D005562:Formazans; D013778:Tetrazolium Salts; C498839:YK2000; C079782:MTT formazan; D004448:Echinomycin; D020929:Mitogen-Activated Protein Kinase Kinases