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 3mg/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.
Rabi
Thangaiyan
T
Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA. Electronic address: trabi@uri.edu.
Banerjee
Sipra
S
Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D019098:Telomerase / Q000037:antagonists & inhibitors*; D014315:Triterpenes / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014315:Triterpenes; C530744:methyl 25-hydroxy-3-oxoolean-12-en-28-oate; D009828:Oleanolic Acid; C509186:TERT protein, human; D019098:Telomerase