Novel semisynthetic triterpenoid AMR-Me inhibits telomerase activity in human leukemic CEM cells and exhibits in vivo antitumor activity against Dalton's lymphoma ascites tumor

Telomerase, a ribonucleoprotein complex of hTERT and hTER, has been reported to be associated with carcinogenesis and multidrug resistance (MDR). Methyl-25-hydroxy-3-oxoolean-12-en-28-oate (AMR-Me) is a novel semisynthetic triterpenoid, derived from a triterpene acid isolated from the stem bark of a tropical tree Amoora rohituka grown wild in India. We examined the role of telomerase in mediating the growth suppression of human acute lymphoblastic leukemic CEM cells by AMR-Me. The results showed that AMR-Me inhibited the growth and viability of CEM cells, induced apoptosis and cell cycle arrest in G(2)+M phase. AMR-Me treatment resulted in suppression of hTERT expression and a concomitant inhibition of telomerase activity. The in vivo antitumor activity of AMR-Me was determined using mice inoculated with Dalton's lymphoma ascites tumor cells. Intraperitoneal administration of the AMR-Me at doses of 1 or 3 mg/kg, increased the survival rate by 121% and 133% respectively, without weight change over the treatment period. Our results suggest that AMR-Me inhibits telomerase activity by decreasing the hTERT expression and induces apoptosis in human lymphoblastic leukemic CEM cells, thus providing the molecular basis for the development of AMR-Me as a novel chemotherapeutic agent against leukemia. (C) 2009 Elsevier Ireland Ltd. All rights reserved.