Cancer Research Program, Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala 695014, India.
Cell Death Dis. 2013 Feb 21;4(2):e505. doi: 10.1038/cddis.2013.26.
5-Fluorouracil (5-FU) is the first rationally designed antimetabolite, which achieves its therapeutic efficacy through inhibition of the enzyme thymidylate synthase (TS), which is essential for the synthesis and repair of DNA. However, prolonged exposure to 5-FU induces TS overexpression, which leads to 5-FU resistance in cancer cells. Several studies have identified curcumin as a potent chemosensitizer against chemoresistance induced by various chemotherapeutic drugs. In this study, we report for the first time, with mechanism-based evidences, that curcumin can effectively chemosensitize breast cancer cells to 5-FU, thereby reducing the toxicity and drug resistance. We found that 10 μM 5-FU and 10 μM curcumin induces a synergistic cytotoxic effect in different breast cancer cells, independent of their receptor status, through the enhancement of apoptosis. Curcumin was found to sensitize the breast cancer cells to 5-FU through TS-dependent downregulation of nuclear factor-κB (NF-κB), and this observation was confirmed by silencing TS and inactivating NF-κB, both of which reduced the chemosensitizing efficacy of curcumin. Silencing of TS suppressed 5-FU-induced NF-κB activation, whereas inactivation of NF-κB did not affect 5-FU-induced TS upregulation, confirming that TS is upstream of NF-κB and regulates the activation of NF-κB in 5-FU-induced signaling pathway. Although Akt/PI3kinase and mitogen-activated protein kinase pathways are activated by 5-FU and downregulated by curcumin, they do not have any role in regulating the synergism. As curcumin is a pharmacologically safe and cost-effective compound, its use in combination with 5-FU may improve the therapeutic index of 5-FU, if corroborated by in vivo studies and clinical trials.
5-氟尿嘧啶（5-FU）是第一个经过合理设计的抗代谢物，通过抑制胸苷酸合成酶（TS）来实现其治疗效果，TS 是 DNA 合成和修复所必需的。然而，长时间暴露于 5-FU 会诱导 TS 过表达，从而导致癌细胞对 5-FU 产生耐药性。多项研究已经表明，姜黄素是一种有效的化学增敏剂，可以对抗多种化疗药物引起的耐药性。在这项研究中，我们首次基于机制证据表明，姜黄素可以有效地使乳腺癌细胞对 5-FU 产生化学敏感性，从而降低毒性和耐药性。我们发现，10μM 的 5-FU 和 10μM 的姜黄素通过增强凋亡，在不同的乳腺癌细胞中产生协同的细胞毒性作用，而与它们的受体状态无关。姜黄素通过 TS 依赖性下调核因子-κB（NF-κB）使乳腺癌细胞对 5-FU 敏感，这一观察结果通过沉默 TS 和使 NF-κB 失活得到了证实，这两种方法都降低了姜黄素的化学增敏作用。沉默 TS 抑制了 5-FU 诱导的 NF-κB 激活，而 NF-κB 的失活并不影响 5-FU 诱导的 TS 上调，这证实了 TS 位于 NF-κB 的上游，调节 5-FU 诱导的信号通路中 NF-κB 的激活。虽然 Akt/PI3 激酶和丝裂原活化蛋白激酶通路被 5-FU 激活并被姜黄素下调，但它们在调节协同作用方面没有任何作用。由于姜黄素是一种药理安全且具有成本效益的化合物，如果在体内研究和临床试验中得到证实，它与 5-FU 联合使用可能会提高 5-FU 的治疗指数。
