Novel function of the thyroid hormone analog tetraiodothyroacetic acid: a cancer chemosensitizing and anti-cancer agent
Novel function of the thyroid hormone analog tetraiodothyroacetic acid: a cancer chemosensitizing and anti-cancer agent
复制标题
DOI：
10.1007/s10456-008-9110-8
复制
发表时间：
2008-09-01
期刊：
影响因子：
9.8
通讯作者：
Mousa, Shaker A.
中科院分区：
文献类型：
--
作者：
Rebbaa, Abdelhadi;Chu, Fei;Mousa, Shaker A.
我们实验室以前的研究表明，甲状腺激素在癌症进展中起着关键作用。此外，发现拮抗这些激素的增殖作用的脱氨基形式四碘甲状腺乙酸（tetraic）通过其抑制细胞增殖和血管生成的能力而具有抗癌功能。本研究的目的是调查Tetrac是否也可以抑制耐药性的发展，耐药性是疾病复发的一个致病因素。Tetrac在体外被证明可以增强来自神经母细胞瘤、骨肉瘤和乳腺癌的耐药肿瘤细胞系对阿霉素、依托泊苷、顺铂和阿司他丁A的细胞反应。tetrac的作用机制不涉及经典耐药基因的表达。然而，放射性标记的多柔比星在细胞中的摄取增强四，这表明一个或多个出口机制的化疗药物被抑制。Tetrac还被发现增强细胞对衰老和凋亡的易感性，这表明该药物可能针对多种耐药机制。Tetrac先前已显示在体外抑制肿瘤细胞增殖。在体内研究报告显示，在脉冲给药方案中的Tetrac是有效的抑制阿霉素耐药的人乳腺癌裸鼠的生长。在该范例中，多柔比星敏感性没有恢复，表明（1）Tetrac对药物敏感性的体外恢复可能与体内耐药现象无关，（2）Tetrac是多柔比星耐药细胞中的有效化疗剂。
Previous studies from our laboratory have demonstrated that thyroid hormones play a key role in cancer progression. In addition, a deaminated form, tetraiodothyroacetic acid (tetrac), that antagonizes the proliferative action of these hormones was found to possess anti-cancer functions through its ability to inhibit cellular proliferation and angiogenesis. The present study was undertaken to investigate whether tetrac could also suppress the development of drug resistance, known as a causative factor of disease relapse. Tetrac was shown to enhance cellular response in vitro to doxorubicin, etoposide, cisplatin, and trichostatin A in resistant tumor cell lines derived from neuroblastoma, osteosarcoma, and breast cancer. The mechanism of action of tetrac did not involve expression of classical drug resistance genes. However, radiolabeled doxorubicin uptake in cells was enhanced by tetrac, suggesting that one or more export mechanisms for chemotherapeutic agents are inhibited. Tetrac was also found to enhance cellular susceptibility to senescence and apoptosis, suggesting that the agent may target multiple drug resistance mechanisms. Tetrac has previously been shown to inhibit tumor cell proliferation in vitro. In vivo studies reported here revealed that tetrac in a pulsed-dose regimen was effective in suppressing the growth of a doxorubicin-resistant human breast tumor in the nude mouse. In this paradigm, doxorubicin-sensitivity was not restored, indicating that (1) the in vitro restoration of drug sensitivity by tetrac may not correlate with in vivo resistance phenomena and (2) tetrac is an effective chemotherapeutic agent in doxorubicin-resistant cells.