Biological activity of the G-quadruplex ligand RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) is associated with telomere capping alteration
Biological activity of the G-quadruplex ligand RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) is associated with telomere capping alteration
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DOI：
10.1124/mol.104.001537
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发表时间：
2004-11-01
影响因子：
3.6
通讯作者：
Biroccio, A
中科院分区：
文献类型：
--
作者：
Leonetti, C;Amodei, S;Biroccio, A
这项研究有两个目标：1）评价新型五环吖啶3，11-二氟-6，8，13-三甲基-8H-喹啉[4，3，2-kl]吖啶甲硫酸盐（RHPS 4）对具有长端粒的人黑素瘤细胞系的生物学效应，以及2）阐明基于G-四链体的端粒酶催化剂诱导的细胞效应与端粒长度/功能障碍之间的关系。已经通过用增加浓度的RHPS 4处理黑素瘤系来评价RHPS 4的细胞药理学作用。在短期处理期间，在所有细胞系中观察到细胞增殖的剂量依赖性抑制。流式细胞仪分析表明，RHPS 4诱导细胞在细胞周期的S-G（2）/M期的剂量依赖性积累。即使在低剂量下，RHPS 4诱导的细胞周期改变也是不可逆的，并且细胞死于凋亡。在高浓度的RHPS 4下，凋亡伴随着衰老表型的诱导：大细胞尺寸、空泡化的细胞质和β-半乳糖苷酶活性。RHPS 4的短期生物活性不是由端粒缩短引起的，而是与端粒功能障碍有关，如端粒融合、多核细胞和典型的末期桥图像。总之，我们的研究结果表明，G-四链体配体RHPS 4可以在端粒长度不依赖的方式，通过其能力，导致端粒加帽改变的功能。
This study had two goals: 1) to evaluate the biological effect of the novel pentacyclic acridine 3,11-difluoro-6,8,13-trimethyl-8H-quino[ 4,3,2-kl] acridinium methosulfate (RHPS4) on human melanoma lines possessing long telomeres, and 2) to elucidate the relationship between G-quadruplex-based telomerase inhibitor-induced cellular effects and telomere length/dysfunction. The cellular pharmacological effects of RHPS4 have been evaluated by treating melanoma lines with increasing concentrations of RHPS4. A dose-dependent inhibition of cell proliferation was observed in all the lines during short-term treatment. Flow cytometric analysis demonstrated that RHPS4 induced a dose-dependent accumulation of cells in the S-G(2)/M phase of cell cycle. The RHPS4-induced cell cycle alteration was irreversible even at low doses, and the cells died from apoptosis. At high RHPS4 concentration, apoptosis was accompanied by the induction of a senescence phenotype: large cell size, vacuolated cytoplasm, and beta-galactosidase activity. The short-term biological activity of RHPS4 was not caused by telomere shortening, but it was associated with telomere dysfunction, in terms of presence of telomeric fusions, polynucleated cells, and typical images of telophase bridge. In conclusion, our results demonstrate that the G-quadruplex ligand RHPS4 can function in a telomere length-independent manner through its ability to cause telomere-capping alteration.