Pharmacodynamics of the G-quadruplex-stabilizing telomerase inhibitor 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl] acridinium methosulfate (RHPS4) in vitro:: Activity in human tumor cells correlates with telomere length and can be enhanced, or antagonized, with cytotoxic agents
Pharmacodynamics of the G-quadruplex-stabilizing telomerase inhibitor 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl] acridinium methosulfate (RHPS4) in vitro:: Activity in human tumor cells correlates with telomere length and can be enhanced, or antagonized, with cytotoxic agents
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DOI：
10.1124/mol.105.013300
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发表时间：
2005-12-01
影响因子：
3.6
通讯作者：
Burger, AM
中科院分区：
文献类型：
--
作者：
Cookson, JC;Dai, FP;Burger, AM
端粒的完整性是维持癌细胞复制能力所必需的，并且是G-四链体稳定药物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）的靶标。我们报告了MCF-7乳腺癌细胞在14至17天内的衰老样生长停滞，以及端粒长度的减少（0.5和1 μ M处理17天后，分别从5.2个端粒（kb）减少到4.7和4.3 kb）。这些效应发生在与长期药物剂量相容的非细胞毒性药物浓度（剂量< 1 μ M，暴露14天）。癌细胞的端粒长度影响其对RHPS 4生长抑制的敏感性：突变型（mt）人端粒酶逆转录酶（hTERT）表达MCF-7细胞[短端粒限制性片段（TRF）长度，1.9kb; IC 50，0.2 μ M]对RHPS 4的敏感性是野生型（wt）hTERT表达的10倍，载体转染的对照细胞（较长的TRF长度5.2 kb; IC 50 2 μ M）在5天SRB测定中。这种关系在一组36个体外生长的人肿瘤异种移植物中得到证实，显示端粒长度和RHPS 4的生长抑制效力之间呈正相关（15天克隆形成测定，r = 0.75）。这些观察结果与由RHPS 4 G-四链体稳定化介导的端粒的保护性加帽状态的丧失一致，从而导致具有较短端粒的细胞的更大易感性。在联合研究中，紫杉醇（Taxol）、阿霉素（Adriamycin）和实验性治疗剂17-（烯丙基氨基）-17-去甲氧基格尔德霉素（抑制90-kDa热休克蛋白）增强了RHPS 4处理的MCF-7细胞的敏感性，而DNA相互作用的替莫唑胺和顺铂拮抗了RHPS 4的作用。我们的研究结果支持联合使用某些类别的细胞毒性抗癌剂与RHPS 4，以提高潜在的临床效益。
Telomeric integrity is required to maintain the replicative ability of cancer cells and is a target for the G-quadruplex-stabilizing drug 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4). We report a senescent-like growth arrest in MCF-7 breast cancer cells, within 14 to 17 days, and a reduction in telomere length ( from 5.2 kilobases (kb) to 4.7 and 4.3 kb after 17 days of treatment at 0.5 and 1 mu M, respectively). These effects occurred at noncytotoxic drug concentrations ( doses < 1 mu M over a 14-day exposure) compatible with long-term drug dosing. The telomere length of cancer cells influences their sensitivity to growth inhibition by RHPS4: mutant (mt) human telomerase reverse transcriptase (hTERT)-expressing MCF-7 cells [short telomere restriction fragment (TRF) length, 1.9 kb; IC50, 0.2 mu M] were 10 times more sensitive to RHPS4 compared with wild-type (wt) hTERT-expressing, vector-transfected control cells ( longer TRF-length 5.2 kb; IC50 2 mu M) in the 5 day SRB assay. This relationship was corroborated in a panel of 36 human tumor xenografts grown in vitro showing a positive correlation between telomere length and growth inhibitory potency of RHPS4 (15-day clonogenic assay, r = 0.75). These observations are consistent with loss of the protective capping status of telomeres mediated by RHPS4 G-quadruplex-stabilization, thus leading to greater susceptibility of cells with shorter telomeres. In combination studies, paclitaxel ( Taxol), doxorubicin ( Adriamycin), and the experimental therapeutic agent 17-(allylamino)-17-demethoxygeldanamycin,which inhibits the 90-kDa heat shock protein, conferred enhanced sensitivity in RHPS4 treated MCF-7 cells, whereas the DNA-interactive temozolomide and cisplatin antagonized the action of RHPS4. Our results support the combined use of certain classes of cytotoxic anticancer agents with RHPS4 to enhance potential clinical benefit.