Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991.
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.
Seimiya
Hiroyuki
H
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan.
Oh-hara
Tomoko
T
Suzuki
Tsuneji
T
Naasani
Imad
I
Shimazaki
Toshiyuki
T
Tsuchiya
Katsutoshi
K
Tsuruo
Takashi
T
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001549:Benzamides / Q000627:therapeutic use*; D015139:Blotting, Southern; D002392:Catechin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002867:Chromones / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008956:Models, Chemical; D010641:Phenotype; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere / Q000502:physiology*; D013997:Time Factors; D020298:U937 Cells; D001616:beta-Galactosidase / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D002867:Chromones; D004791:Enzyme Inhibitors; C470199:MST 199; C470198:MST 295; C470197:MST 312; D002392:Catechin; C045651:epigallocatechin gallate; D019098:Telomerase; D001616:beta-Galactosidase