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

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 microM). 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 microM. Similarly, cell proliferation inhibition by DMNQ S-52 was masked by caspase inhibitor Z-Asp-Glu-Val-Asp-fluoromethylketone (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.

• Authors: Soo Jin Lee, Hiroaki Sakurai, Keiichi Koizumi, Gyu Yong Song, Yong Soo Bae, Hyung-Min Kim, Kyung-Sun Kang, Young-Joon Surh, Ikuo Saiki, Sung Hoon Kim
• Journal: Cancer letters (Cancer Lett) Vol. 233 Issue 1 Pg. 57-67 (Feb 20 2006) ISSN: 0304-3835 [Print] Ireland
• PMID: 15893420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-(1-hydroxyimino-4-methylpentyl)-5,8-dimethoxy-1,4-naphthoquinone
• Annexin A5
• Antineoplastic Agents
• Naphthoquinones
• Mitogen-Activated Protein Kinases
• Caspases

Topics

• Animals
• Annexin A5 (analysis)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Carcinoma, Lewis Lung (drug therapy, enzymology, pathology)
• Caspases (physiology)
• Cell Proliferation (drug effects)
• Enzyme Activation
• Female
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (physiology)
• Naphthoquinones (pharmacology, therapeutic use)