Rabi Thangaiyan, Banerjee Sipra
Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
Cancer Lett. 2009 Jun 18;278(2):156-163. doi: 10.1016/j.canlet.2009.01.003. Epub 2009 Feb 6.
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.
端粒酶是一种由人端粒酶逆转录酶（hTERT）和人端粒酶RNA（hTER）组成的核糖核蛋白复合体，据报道其与肿瘤发生和多药耐药性（MDR）相关。甲基-25-羟基-3-氧代齐墩果-12-烯-28-酸甲酯（AMR-Me）是一种新型半合成三萜类化合物，它源自从印度野生生长的热带树木罗希脱木（Amoora rohituka）茎皮中分离出的一种三萜酸。我们研究了端粒酶在介导AMR-Me对人急性淋巴细胞白血病CEM细胞生长抑制中的作用。结果显示，AMR-Me抑制了CEM细胞的生长和活力，诱导细胞凋亡并使细胞周期停滞于G(2)+M期。AMR-Me处理导致hTERT表达受抑，并伴随端粒酶活性的抑制。利用接种了道尔顿淋巴瘤腹水瘤细胞的小鼠测定了AMR-Me的体内抗肿瘤活性。腹腔注射剂量为1或3mg/kg的AMR-Me，分别使存活率提高了121%和133%，且在治疗期间体重未发生变化。我们的结果表明，AMR-Me通过降低hTERT表达来抑制端粒酶活性，并诱导人淋巴细胞白血病CEM细胞凋亡，从而为将AMR-Me开发成一种新型抗白血病化疗药物提供了分子基础。
