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MAPK regulation and caspase activation are required in DMNQ S-52 induced apoptosis in Lewis lung carcinoma cells

Cited 6 time in Web of Science Cited 7 time in Scopus
Authors
Lee, Soo Jin; Sakurai, Hiroaki; Koizumi, Keiichi; Song, Gyu Yong; Bae, Yong Soo; Kim, Hyung-Min; Kang, Kyung-Sun; Surh, Young-Joon; Saiki, Ikuo; Kim, Sung Hoon
Issue Date
2006-02
Citation
Cancer Letters, Vol.233 No.1, pp.57-67
Keywords
DMNQ S-52apoptosisMAPKcaspasesLLC cellsimmunohistochemistry
Abstract
6-(1-Hydroxyimino-4-methylpentyl)5,8-dimethyoxy 1.4-naphthoquinone S-52 (DMNQ S-52) was reported to have cytotoxic activity against L1210 leukemia cells. In the present study, we investigated the apoptotic mechanism of DMNQ S-52 in vitro and in vivo in murine solid cancer cells. DMNQ S-52 exerted cytotoxicity against Lewis lung carcinoma (LLC) Cells (IC50= 12.3 mu M). DMNQ S-52 increased Annexin V positive cell population in a concentration-dependent manner. DMNQ S-52 also induced apoptosis through caspase-mediated pathway, including activation of caspase-3, cleavage of Poly(ADP-ribose) polymerase (PARP) and decreased expression of Bcl-2 in LLC cells in a time and concentration-dependent fashion. DMNQ S-52 activated the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 as well as abrogated the expression of extracellular signal-regulated kinase (ERK) in a time-dependent manner at 10 mu M. Similarly, cell proliferation inhibition by DMNQ S-52 was masked by caspase inhibitor Z-Asp-Glu-Val-Asp-fluoromethy I ketone (Z-VAD-FMK), JNK inhibitor SP600125 and p38 inhibitor SB203580, but not by MEK inhibitor U0126. Furthermore, i.p. administration of DMNQ S-52 at 5 mg/kg resulted in a potent inhibition of the growth of LLC cells implanted on the right flank of C57BL/6 mice compared to untreated control. Immunohistochemical analysis revealed the decreased tumor, cell proliferation and increased tumor cell apoptosis in DMNQ S-52 treated tumor sections using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and proliferation cell nuclear antigen (PCNA). Taken together, these findings demonstrate that DMNQ S-52 may exhibit anti-tumor activity by inducing apoptosis via caspases and mitogen activated protein (MAP) kinase-dependent pathways. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
ISSN
0304-3835
URI
https://hdl.handle.net/10371/172747
DOI
https://doi.org/10.1016/j.canlet.2005.02.042
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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