2005 Fiscal Year Final Research Report Summary
Chemogenomic approach for elucidation and control of intracellular signal transductions
| Project/Area Number |
15310150
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Living organism molecular science
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| Research Institution | Osaka University |
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Principal Investigator |
KATO Nobuo Osaka University, Institute of Scientific and Industrial Sciences, Professor, 産業科学研究所, 教授 (50150537)
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| Co-Investigator(Kenkyū-buntansha) |
NITTA Hajime Osaka University, Institute of Scientific and Industrial Sciences, Research Associate, 産業科学研究所, 助手 (20107098)
KAWANO Tomikazu Osaka University, Institute of Scientific and Industrial Sciences, Research Associate, 産業科学研究所, 助手 (30283807)
SASSA Takeshi Yamagata University, Faculty of Agriculture, Professor Emeritus, 農学部, 名誉教授 (80023456)
TANAKA Junji Kyushu University, Institute for Materials Chemistry and Engineering, Research Associate, 先導物質化学研究所, 助手 (60155140)
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| Project Period (FY) |
2003 – 2005
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| Keywords | Anti-cancer Activity / Differentiation-inducing Activity / Intracellular Signal Transduction / Diterpene Glycoside / Cotylenin / Fusicoccin / 14-3-3 Protein / Chemogenomics |
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| Research Abstract |
Forward chemogenomic studies for anti-cancer activity of cotylenin (CN), a fusicoccane type of diterpene glycoside, and reverse chemogenomic investigation on 14-3-3 proteins, regulatory proteins in intracellular signal transductions, have been carried out. Results obtained are summarized below :
1. Significant synergistic effects of CN with interferon α or rapamicin are observed on ovary and breast cancer cells, respectively. With these combined treatment, growth of tumors were effectively reduced in xenografts on mice.
2. As a polar congener of fusicoccins (FC), 3α-hydroxyfusicoccin J has been isolated from fusicoccin-producing fungus, Phomopsis amygdali. This compound was quite useful for Structure-Activity=Relationship (SAR) studies on anti-cancer activities of CN/FC class of compounds.
3. CN and FC have identical activities on plant tissues. However, only CN has a strong differentiation-inducing activity of human myeloid leukemia cell line (HL-60). FC exhibits cytotoxicity instead. Detailed SAR studies lead the conclusion that the 12-OH of FC interferes the activity.
4. According to the conclusion of SAR studies, we have succeeded in synthesizing 12-deoxyfusicoccin derivatives of which activities are as potent as that of CN.
5. Reverse chemogenomic investigation revealed that CN can cross-link with 14-3-3 sigma as an isoform selective fashion and strength the binding ability of this isoform toward its partner phosphor-peptide.
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