Telomere Shortening and Growth Inhibition of Human Cancer Cells by Novel Synthetic Telomerase Inhibitors MST-312, MST-295, and MST-199 1 Supported in part by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan. 1

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 β-galactosidase activity. Particularly, in the case of MST-312, the effective dose required for the telomere shortening was 1–2 μ m , which was 15- to 20-fold lower than that of EGCG. These compounds may provide a novel chemotherapeutic strategy for the treatment of cancers.