A novel aspirin prodrug inhibits NFκB activity and breast cancer stem cell properties.
A novel aspirin prodrug inhibits NFκB activity and breast cancer stem cell properties.
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DOI：
10.1186/s12885-015-1868-7
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发表时间：
2015-11-04
期刊：
影响因子：
3.8
通讯作者：
Frasor J
中科院分区：
文献类型：
--
作者：
Kastrati I;Litosh VA;Zhao S;Alvarez M;Thatcher GR;Frasor J
环氧合酶（考克斯）/前列腺素和核因子κB（NFκB）通路的激活可促进乳腺肿瘤的发生、生长以及向耐药和转移的进展。因此，抗炎药物已被广泛探索作为化学预防剂和抗炎剂。特别是阿司匹林（阿萨），与乳腺癌发病率降低有关，但胃肠道毒性限制了其有效性。为了提高效力并使毒性最小化，已经开发了阿萨酯前药，其中阿萨的羧酸被掩蔽并且可以掺入辅助药效团。迄今为止，阿萨和阿萨前药的作用主要归因于考克斯抑制和前列腺素产生减少。然而，据报道阿萨在非常高的剂量下也能抑制NFκB通路。阿萨前体药物是否能抑制NFκB信号传导仍然相对未被探索。合成了阿萨前药文库，并筛选了抑制NFκB活性和癌症干细胞样细胞（CSC）特性的ASA前药，CSC是侵袭性乳腺癌的重要PGE 2和NFκ B依赖性表型。通过双荧光素酶试验、RT-QPCR、p65 DNA结合活性和Western印迹测定NFκB活性的抑制。通过乳腺球生长、CD 44 + CD 24 −免疫表型和有限稀释下的致瘤性确定CSC特性的抑制。虽然我们鉴定了多种能够抑制NFκB通路的阿萨前药，但有几种与细胞毒性有关。特别令人感兴趣的是GTCpFE，一种以富马酸盐为辅助药效团的阿萨前药。该前药有效抑制NFκB活性，无先天性细胞毒性。此外，GTCpFE通过减少乳腺球生长和CD 44 + CD 24 −免疫表型表现出选择性抗CSC活性。此外，GTCpFE预处理的细胞致瘤性较低，并且当肿瘤确实形成时，潜伏期增加并且生长速率降低。GTCpFE的结构-活性关系表明，在阿萨前药的背景下，富马酸盐对抗NF κB活性至关重要，而阿萨和富马酸盐部分均有助于减弱乳腺球生长。这些结果确立了GTCpFE作为新型ASA和基于琥珀酸盐的抗炎药物的原型：（i）能够靶向CSC，（ii）可以开发为乳腺癌的化学预防或治疗剂。本文的在线版本（doi：10.1186/s12885-015-1868-7）包含补充材料，可供授权用户使用。
Activation of cyclooxygenase (COX)/prostaglandin and nuclear factor κB (NFκB) pathways can promote breast tumor initiation, growth, and progression to drug resistance and metastasis. Thus, anti-inflammatory drugs have been widely explored as chemopreventive and antineoplastic agents. Aspirin (ASA), in particular, is associated with reduced breast cancer incidence but gastrointestinal toxicity has limited its usefulness. To improve potency and minimize toxicity, ASA ester prodrugs have been developed, in which the carboxylic acid of ASA is masked and ancillary pharmacophores can be incorporated. To date, the effects of ASA and ASA prodrugs have been largely attributed to COX inhibition and reduced prostaglandin production. However, ASA has also been reported to inhibit the NFκB pathway at very high doses. Whether ASA prodrugs can inhibit NFκB signaling remains relatively unexplored. A library of ASA prodrugs was synthesized and screened for inhibition of NFκB activity and cancer stem-like cell (CSC) properties, an important PGE2-and NFκB-dependent phenotype of aggressive breast cancers. Inhibition of NFκB activity was determined by dual luciferase assay, RT-QPCR, p65 DNA binding activity and Western blots. Inhibition of CSC properties was determined by mammosphere growth, CD44+CD24−immunophenotype and tumorigenicity at limiting dilution. While we identified multiple ASA prodrugs that are capable of inhibiting the NFκB pathway, several were associated with cytotoxicity. Of particular interest was GTCpFE, an ASA prodrug with fumarate as the ancillary pharmacophore. This prodrug potently inhibits NFκB activity without innate cytotoxicity. In addition, GTCpFE exhibited selective anti-CSC activity by reducing mammosphere growth and the CD44+CD24−immunophenotype. Moreover, GTCpFE pre-treated cells were less tumorigenic and, when tumors did form, latency was increased and growth rate was reduced. Structure-activity relationships for GTCpFE indicate that fumarate, within the context of an ASA prodrug, is essential for anti-NFκB activity, whereas both the ASA and fumarate moieties contributed to attenuated mammosphere growth. These results establish GTCpFE as a prototype for novel ASA-and fumarate-based anti-inflammatory drugs that: (i) are capable of targeting CSCs, and (ii) may be developed as chemopreventive or therapeutic agents in breast cancer. The online version of this article (doi:10.1186/s12885-015-1868-7) contains supplementary material, which is available to authorized users.