Leptosins isolated from marine fungus Leptoshaeria species inhibit DNA topoisomerases I and/or II and induce apoptosis by inactivation of Akt/protein kinase B
| Autor: | Banri Yamanoha, Atsushi Numata, Toshiwo Andoh, Takao Yamori, Masahito Shinomi, Tetsuo Sugahara, Izumi Yamashita, Noriko Sasaki-Takahashi, Miyako Yanagihara, Seiko Yamamoto, Masashi Hayashida |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
education Apoptosis Topoisomerase-I Inhibitor Kidney Cell Line Indole Alkaloids medicine Humans Topoisomerase II Inhibitors Viability assay Enzyme Inhibitors Protein kinase B health care economics and organizations PI3K/AKT/mTOR pathway biology Topoisomerase Fungi General Medicine In vitro Oncology Biochemistry biology.protein Topoisomerase I Inhibitors Topoisomerase-II Inhibitor Proto-Oncogene Proteins c-akt hormones hormone substitutes and hormone antagonists Camptothecin medicine.drug |
| Zdroj: | Cancer Science. 96:816-824 |
| ISSN: | 1349-7006 1347-9032 |
| Popis: | DNA topoisomerases (topo) I and II are molecular targets of several potent anticancer agents. Thus, inhibitors of these enzymes are potential candidates or model compounds for anticancer drugs. Leptosins (Leps) F and C, indole derivatives, were isolated from a marine fungus, Leptoshaeria sp. as cytotoxic substances. In vitro cytotoxic effects of Lep were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based viability assay. Lep F inhibited the activity of topos I and II, whereas Lep C inhibited topo I in vitro. Interestingly both of the compounds were found to be catalytic inhibitors of topo I, as evidenced by the lack of stabilization of reaction intermediate cleavable complex (CC), as camptothecin (CPT) does stabilize. Furthermore, Lep C inhibited the CC stabilization induced by CPT in vitro. In vivo band depletion analysis demonstrated that Lep C likewise appeared not to stabilize CC, and inhibited CC formation by CPT, indicating that Lep C is also a catalytic inhibitor of topo I in vivo. Cell cycle analysis of Lep C-treated cells showed that Lep C appeared to inhibit the progress of cells from G(1) to S phase. Lep C induced apoptosis in RPMI8402 cells, as revealed by the accumulation of cells in sub-G(1) phase, activation of caspase-3 and the nucleosomal degradation of chromosomal DNA. Furthermore, Leps F and C inhibited the Akt pathway, as demonstrated by dose-dependent and time-dependent dephosphorylation of Akt (Ser473). Our study shows that Leps are a group of anticancer chemotherapeutic agents with single or dual catalytic inhibitory activities against topos I and II. |
| Databáze: | OpenAIRE |
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