HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) An addition or correction has been published Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tanikawa, M. Articles by Nakanishi, M. Search for Related Content PubMed PubMed Citation Articles by Tanikawa, M. Articles by Nakanishi, M. Social Bookmarking                      What's this?

J Biol Chem, Vol. 273, Issue 29, 18522-18527, July 17, 1998

Potent Prostaglandin A₁ Analogs That Suppress Tumor Cell Growth through Induction of p21 and Reduction of Cyclin E

Motoki Tanikawa^§, Kazuo Yamada^§, Kaoru Tominaga, Hirobumi Morisaki, Yoko Kaneko, Kyoji Ikeda, Masaaki Suzuki^¶, Toshihiro Kiho, Keiichiro Tomokiyo^¶, Kyoji Furuta^¶, Ryoji Noyori, and Makoto Nakanishi

From the  Department of Geriatric Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka-cho, Obu, Aichi 474, the ^§ Department of Neurosurgery, Nagoya City University School of Medicine, Nagoya, Aichi 467, the ^¶ Department of Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-11, and the  Department of Chemistry and Molecular Chirality Research Unit, Nagoya University, Chikusa, Nagoya 464-01, Japan

Although the cyclopentenone prostaglandin A₁ (PGA₁) is known to arrest the cell cycle at the G₁ phase in vitro and to suppress tumor growth in vivo, its relatively weak activity limits its usefulness in cancer chemotherapy. In an attempt to develop antitumor drugs of greater potency and conspicuous biological specificity, we synthesized novel analogs based on the structure of PGA₁. Of the newly synthesized analogs, 15-epi-⁷-PGA₁ methyl ester (NAG-0092), 12-iso-⁷-PGA₁ methyl ester (NAG-0093), and ent-⁷-PGA₁ methyl ester (NAG-0022) possess a cross-conjugated dienone structure around the five-member ring with unnatural configurations at C(12) and/or C(15) and were found to be far more potent than native PGA₁ in inhibiting cell growth and causing G₁ arrest in A172 human glioma cells. These three analogs induced the expression of p21 at both RNA and protein levels in a time- and dose-dependent fashion. Kinase assays with A172 cells treated with these analogs revealed that both cyclin A- and E-dependent kinase activities were markedly reduced, although cyclin D1-dependent kinase activity was unaffected. Immunoprecipitation-Western blot analysis showed that the decrease in cyclin A-dependent kinase activity was due to an increased association of p21 with cyclin A-cyclin-dependent kinase 2 complexes, whereas the decrease in cyclin E-dependent activity was due to a combined mechanism involving reduction in cyclin E protein itself and increased association of p21. Thus, these newly synthesized PGA₁ analogs may prove to be powerful tools in cancer chemotherapy as well as in investigations of the structural basis of the antiproliferative activity of A series prostaglandins.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				J. L. Oliva, D. Perez-Sala, A. Castrillo, N. Martinez, F. J. Canada, L. Bosca, and J. M. Rojas The cyclopentenone 15-deoxy-Delta 12,14-prostaglandin J2 binds to and activates H-Ras PNAS, April 15, 2003; 100(8): 4772 - 4777. [Abstract] [Full Text] [PDF]

				D. A. Maria, O. G. Ribeiro, K. F. Pizzocaro, M. De Franco, W. K. Cabrera, N. Starobinas, V. Gallois, M. Siqueira, M. Seman, and O. M. Ibanez Resistance to melanoma metastases in mice selected for high acute inflammatory response Carcinogenesis, February 1, 2001; 22(2): 337 - 342. [Abstract] [Full Text] [PDF]

				P. J. Moos, K. Edes, and F. A. Fitzpatrick Inactivation of wild-type p53 tumor suppressor by electrophilic prostaglandins PNAS, July 19, 2000; (2000) 160241897. [Abstract] [Full Text]

				K. Tominaga, H. Morisaki, Y. Kaneko, A. Fujimoto, T. Tanaka, M. Ohtsubo, M. Hirai, H. Okayama, K. Ikeda, and M. Nakanishi Role of Human Cds1 (Chk2) Kinase in DNA Damage Checkpoint and Its Regulation by p53 J. Biol. Chem., October 29, 1999; 274(44): 31463 - 31467. [Abstract] [Full Text] [PDF]

				R. DONNELLAN and R. CHETTY Cyclin E in human cancers FASEB J, May 1, 1999; 13(8): 773 - 780. [Abstract] [Full Text]

				T. Murai, Y. Nakagawa, H. Maeda, and K. Terada Altered Regulation of Cell Cycle Machinery Involved in Interleukin-1-induced G1 and G2 Phase Growth Arrest of A375S2 Human Melanoma Cells J. Biol. Chem., February 23, 2001; 276(9): 6797 - 6806. [Abstract] [Full Text] [PDF]

				P. J. Moos, K. Edes, and F. A. Fitzpatrick Inactivation of wild-type p53 tumor suppressor by electrophilic prostaglandins PNAS, August 1, 2000; 97(16): 9215 - 9220. [Abstract] [Full Text] [PDF]