The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function
The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function
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DOI：
10.1158/0008-5472.can-04-2910
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发表时间：
2005-02-15
期刊：
影响因子：
11.2
通讯作者：
Neidle, S
中科院分区：
文献类型：
--
作者：
Burger, AM;Dai, FP;Neidle, S
干扰端粒酶和端粒的维护正在成为一个有吸引力的抗癌治疗的目标。配体诱导的端粒DNA单链3'突出端的G-四链体形成的稳定化抑制端粒酶催化端粒DNA合成和加帽端粒末端。我们在这里报告的3，6，9-三取代吖啶化合物，BRACO-19，在体外和体内对端粒酶功能的影响。在具有非常短的端粒（2.7kb）的人子宫癌细胞系UXF 1138 L中评价BRACO-19的生物活性。在体外实验中，24小时后，细胞核中人端粒酶逆转录酶（hTERT）的表达急剧下降，15天后，细胞衰老和生长完全停止，端粒缩短约1.5倍。0.4 KB.在体内，BRACO-19作为单一药剂在皮下注射中对早期（68 mm 3）肿瘤具有高度活性。由UXF 1138 L细胞建立的生长异种移植模型，如果以2 mg/kg/天腹膜内长期给予BRACO-19，与对照组相比产生96%的生长抑制，伴随部分消退（P < 0.018）。异种移植组织的免疫染色显示，这种反应是由细胞核hTERT蛋白表达的丧失和端粒功能障碍的非典型有丝分裂的增加引起的。观察到细胞质hTERT表达及其与泛素的共定位，表明hTERT与泛素结合，并在BBAC 0 -19处理后靶向增强降解。这与诱导端粒酶从端粒移位的模型是雅阁的。本文提供的体外和体内数据与G-四链体结合配体BRACO-19通过抑制端粒酶的加帽和催化功能产生抗癌作用一致。
Interference with telomerase and telomere maintenance is emerging as an attractive target for anticancer therapies. Ligand-induced stabilization of G-quadruplex formation by the telomeric DNA single-stranded 3' overhang inhibits telomerase from catalyzing telomeric DNA synthesis and from capping telomeric ends. We report here the effects of a 3,6,9-trisubstituted acridine compound, BRACO-19, on telomerase function in vitro and in vivo. The biological activity of BRACO-19 was evaluated in the human uterus carcinoma cell line UXF1138L, which has very short telomeres (2.7 kb). In vitro, nuclear human telomerase reverse transcriptase (hTERT) expression was drastically decreased after 24 hours, induction of cellular senescence and complete cessation of growth was seen after 15 days, paralleled by telomere shortening of ca. 0.4 kb. In vivo, BRACO-19 was highly active as a single agent against early-stage (68 mm 3) tumors in a s.c. growing xenograft model established from UXF1138L cells, if given chronically at 2 mg per kg per day i.p. BRACO-19 produced growth inhibition of 96% compared with controls accompanied by partial regressions (P < 0.018). Immunostaining of xenograft tissues showed that this response was paralleled by loss of nuclear hTERT protein expression and an increase in atypical mitoses indicative of telomere dysfunction. Cytoplasmic hTERT expression and its colocalization with ubiquitin was observed suggesting that hTERT is bound to ubiquitin and targeted for enhanced degradation upon BBACO-19 treatment. This is in accord with a model of induced displacement of telomerase from the telomere. The in vitro and in vivo data presented here is consistent with the G-quadruplex binding ligand BRACO-19 producing an anticancer effect by inhibiting the capping and catalytic functions of telomerase.