Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991.

Abstract

Epidemiological studies suggest potent anticancer effects of tea catechins. Previously, we have reported (I. Naasani et aL, Biochem. Biophys. Res. Commun., 249: 391-396, 1998) that epigallocatechin gallate (EGCG), a major tea catechin, strongly and directly inhibits telomerase, a ribonucleoprotein that maintains telomeres and has been implicated in tumorigenesis. Here, we describe newly synthesized compounds MST-312, MST-295, and MST-199, as more effective telomerase inhibitors than EGCG. Continuous treatment of human monoblastoid leukemia U937 cells with a nontoxic dose of each drug caused progressive telomere shortening and eventual reduction of growth rate accompanied by induction of the senescence-associated beta-galactosidase activity. Particularly, in the case of MST-312, the effective dose required for the telomere shortening was 1-2 microM, which was 15- to 20-fold lower than that of EGCG. These compounds may provide a novel chemotherapeutic strategy for the treatment of cancers.

• Authors: Hiroyuki Seimiya, Tomoko Oh-hara, Tsuneji Suzuki, Imad Naasani, Toshiyuki Shimazaki, Katsutoshi Tsuchiya, Takashi Tsuruo
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 1 Issue 9 Pg. 657-65 (Jul 2002) ISSN: 1535-7163 [Print] United States
• PMID: 12479362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Chromones
• Enzyme Inhibitors
• MST 199
• MST 295
• MST 312
• Catechin
• epigallocatechin gallate
• Telomerase
• beta-Galactosidase

Topics

• Antineoplastic Agents (therapeutic use)
• Apoptosis
• Benzamides (therapeutic use)
• Blotting, Southern
• Catechin (analogs & derivatives, therapeutic use)
• Chromones (therapeutic use)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (therapeutic use)
• Humans
• Models, Chemical
• Phenotype
• Telomerase (antagonists & inhibitors)
• Telomere (physiology)
• Time Factors
• U937 Cells
• beta-Galactosidase (metabolism)