DC-81-enediyne induces apoptosis of human melanoma A375 cells: involvement of the ROS, p38 MAPK, and AP-1 signaling pathways View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2013-01-05

AUTHORS

Chung-Yu Chen, Yin-Kai Chen, Jeh-Jeng Wang, Chia-Chen Hsu, Feng-Yuan Tsai, Ping-Jyun Sung, Hsien-Chang Lin, Long-Sen Chang, Wan-Ping Hu

ABSTRACT

Melanoma is one of the most chemoresistant cancers in patient care. The remission rate of current therapy remains low. DC-81, an antitumor antibiotic produced by Streptomyces species, belongs to pyrrolo[2,1-c][1,4]benzodiazepine (PBD), which is a potent inhibitor of nucleic acid synthesis. An enediyne contains either DNA intercalating groups or DNA minor groove binding functions and these are potent DNA-damaging agents due to their ability to generate benzenoid diradicals. We have previously reported an efficient synthesis and antitumor activity of a series of novel PBD hybrids linked with enediyne. The purpose of this study was to examine the mechanism of the antiproliferative effect of DC-81-enediyne agent on human melanoma A375 cells. DC-81-enediyne induced an increase in Ca2+ level and reactive oxygen species (ROS) generation as detected by flow cytometric assay. Western blot analysis showed that DC-81-enediyne induced the phosphorylation of p38 and activating transcription factor 2 (ATF-2). By using the luciferase reporter assay, activating protein-1 (AP-1) activity was further enhanced after A375 cells were treated with graded concentrations of DC-81-enediyne. DC-81-enediyne treatment-induced A375 cell apoptosis was significantly abrogated by the addition of Ca2+, ROS, and p38 inhibitors. Collectively, our studies indicate that DC-81-enediyne induces A375 cell apoptosis through an increased Ca2+ and ROS generation, which involves p38 phosphorylation and enhanced ATF-2/AP-1 expressions, leading to caspase-3 activity, poly(ADP-ribose)polymerase cleavage, M30 CytoDeath staining, and subsequent apoptotic cell death. More... »

PAGES

85-99

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10565-012-9238-6

DOI

http://dx.doi.org/10.1007/s10565-012-9238-6

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1038050526

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23292217


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