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

• Published in: Molecular cancer therapeutics Vol. 1; no. 9; pp. 657 - 665
• Main Authors: Seimiya, Hiroyuki, Oh-hara, Tomoko, Suzuki, Tsuneji, Naasani, Imad, Shimazaki, Toshiyuki, Tsuchiya, Katsutoshi, Tsuruo, Takashi
• Format: Journal Article
• Language: English
• Published: United States 01.07.2002
• Subjects: Antineoplastic Agents - therapeutic use; Apoptosis; Benzamides - therapeutic use; beta-Galactosidase - metabolism; Blotting, Southern; Catechin - analogs & derivatives; Catechin - 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
• ISSN: 1535-7163

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.