2007 Fiscal Year Final Research Report Summary
Search of cell cycle regulator as an anti-cancer agent, from marine invertebrates
| Project/Area Number |
18590003
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Chemical pharmacy
|
|---|
| Research Institution | Hyogo University of Health Sciences (2007)
Osaka University (2006) |
|---|
Principal Investigator |
AOKI Shunji Hyogo University of Health Sciences, Department of Pharmacy, professor (60252699)
|
|---|
| Project Period (FY) |
2006 – 2007
|
| Keywords | cdk inhibitor / p21 / cell cycle / aaptamine / cryntolepine / secaronic acid D / anti-cancer activity |
|---|
| Research Abstract |
P21 was originally identified as a target protein of p53 and then found to inhibit the activity of Cdk-cyclin complexes, thereby regulating cell cycle as a brake. The p21 expression is mainly controlled by diverse mechanisms in a p53-dependent manner. Due to accumulating evidence that p53 is mutated in many human cancer cells, the mutation of p53 has been recognized as one of the major events in carcinogenesis. However, it appears p21 is rarely mutated in human tumors. Therefore, the agents that induce p21 expression through a p53-independent pathway might contribute to cancer prevention or treatment.
Recently, we established a bioassay method using p53-negative human osteosarcoma MG63 cells to search for compounds that activate the p21 promoter in a p53-independent manner. On the guidance of this bioassay, we isolated aaptamine, a marine alkaloid, cryptolepine, a plant alkaloid and secaronic acid D, a bacterial polyketide as active components. Aaptamine activates p21 promoter stably transfected in MG63 cells at the concentrations of 20-50 μg/ml. Expression of p21 in wild-type MG63 cells also increased with aaptamine treatment. The 48 hr treatment of aaptamine induced G2/M arrest of cell cycle in MG63 cells. Furthermore, responsive elements in p21 promote of aaptamine were analyzed. The full length p21 promoter and a series of deleted or mutated constructs fused with luciferase reporter were transiently expressed in MG63 cells, and the cells were treated with aaptamine, showing that Sp1-3, Sp1-4, and Sp1-5, -6 play important roles in the activation of p21 promoter by aaptamine. In conclusion, our investigation indicated that aaptamine activates the p21 promoter through Sp 1 sites between -82 and -50 by and therefore induces p21 expression in a p53-independent manner.
|
Research Products
(20 results)
-
-
-
-
-
-
-
-
-
-
-
-
-
[Journal Article] Bastadin 6, a Spongean Brominated Tyrosine Derivative, Inhibits Tumor Angiogenesis by Inducing Selective Apoptosis to Endothelial Cells2006
Author(s)
S. Aoki, S-H. Cho, M. Ono, T. Kuwano, S. Nakao, M. Kuwano, S. Nakagawa, JQ. Gao, T. Mayumi, M. Shibuya, M. Kobayashi
-
Journal Title
ANTI-CANCER DRUGS 17
Pages: 269-278
Description
「研究成果報告書概要(欧文)」より
-
[Journal Article] Cortistatins A, B, C, and D, Anti-Angiogenic Steroidal Alkaloids, from the Marine Sponge Corticium simplex.2006
Author(s)
S. Aoki, Y. Watanabe, M. Sanagawa, A. Setiawan, N. Kotoku, M. Kobayashi
-
Journal Title
J. Am. Chem. Soc. 128
Pages: 3148-3149
Description
「研究成果報告書概要(欧文)」より
-
-
-
-
[Journal Article] A novel synthetic drug, LB-18, closely related to lembehyne-A derived from a marine sponge, induces caspase-independent cell death to human neuroblastoma cells.2006
Author(s)
M. Izumi, S. Yogosawa, S. Aoki, H. Watanabe, J. Kamiyama, Y. Takahara, Y. Sowa, M. Kobayashi, H. Hosoi, T. Sugimoto, T. Sakai
-
Journal Title
INTERNATIONAL JOURNAL OF ONCOLOGY 29
Pages: 169-173
Description
「研究成果報告書概要(欧文)」より
-
-
