Synergistic Effects of Topoisomerase I Inhibitor, SN38, on Fas-mediated Apoptosis

Inhibitors of topoisomerase I, such as camptothecin, have proven to be among the most promising new classes of anti-neoplastic agents introduced into the clinical setting in recent years. Irinotecan (CPT-11) is one of the most widely used camptothecin analogs and is converted to form the active meta...

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Bibliographic Details
Published in:Anticancer research 2010-10, Vol.30 (10), p.3911-3917
Main Authors: YAN CAO, JIN, Zhe-Xiong, MASAKI, Yasufumi, FUKUSHIMA, Yoshihiko, FUJITA, Yoshimasa, NAKAJIMA, Hideo, OKAZAKI, Toshiro, UMEHARA, Hisanori, TONG, Xiao-Peng, SUN YUE, SAKAI, Tomoyuki, KAWANAMI, Takafumi, SAWAKI, Toshioki, MIKI, Miyuki, IWAO, Haruka, NAKAJIMA, Akio
Format: Article
Language:English
Subjects:
Adjuvants
Animals
Antibodies, Monoclonal - pharmacology
Apoptosis - drug effects
Ataxia Telangiectasia Mutated Proteins
Biological and medical sciences
Camptothecin - analogs & derivatives
Camptothecin - pharmacology
Caspase 3 - metabolism
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Checkpoint Kinase 1
DNA-Binding Proteins - metabolism
Drug Synergism
Enzyme Activation - drug effects
fas Receptor - genetics
fas Receptor - immunology
Humans
Lymphoma, T-Cell - drug therapy
Lymphoma, T-Cell - enzymology
Lymphoma, T-Cell - immunology
Lymphoma, T-Cell - pathology
Medical sciences
Mice
Protein Kinases - metabolism
Protein-Serine-Threonine Kinases - metabolism
Topoisomerase I Inhibitors - pharmacology
Tumor Suppressor Protein p53 - metabolism
Tumor Suppressor Proteins - metabolism
Tumors
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Summary:Inhibitors of topoisomerase I, such as camptothecin, have proven to be among the most promising new classes of anti-neoplastic agents introduced into the clinical setting in recent years. Irinotecan (CPT-11) is one of the most widely used camptothecin analogs and is converted to form the active metabolite SN-38. The present study was designed to explore apoptosis induced by SN38 and anti-Fas antibody (CH11) in WR/Fas-SMS1 cells and its possible mechanisms. The results demonstrate that combination of SN38 and CH11 synergistically enhanced cell apoptosis in WR/Fas-SMS1 cells. Western blotting analysis showed that combination of SN38 and CH11 activated the ATM-Chk1-p53 pathway, increased protein expression of phospho-p53 and cleavaged caspase-3, but down-regulated expression of phospho-p21. Our data suggest that combination of SN38 and CH11 enhanced apoptosis through down-regulation of p21 phosphorylation. In conclusion, inhibition of p21 could be a new adjuvant approach in cancer therapy.
ISSN:0250-7005
1791-7530