Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Cosenza, Italy.
Department of Biology, Ecology and Earth Sciences, University of Calabria, Rende, Cosenza, Italy.
Mol Cancer Res. 2018 Jun;16(6):923-934. doi: 10.1158/1541-7786.MCR-17-0662. Epub 2018 Mar 9.
Breast cancer is a complex and heterogeneous disease, with distinct histologic features dictating the therapy. Although the clinical outcome of breast cancer patients has been considerably improved, the occurrence of resistance to common endocrine and chemotherapy treatments remains the major cause of relapse and mortality. Thus, efforts in identifying new molecules to be employed in breast cancer therapy are needed. As a "faster" alternative to reach this aim, we evaluated whether lamotrigine, a broadly used anticonvulsant, could be "repurposed" as an antitumoral drug in breast cancer. Our data show that lamotrigine inhibits the proliferation, the anchorage-dependent, and independent cell growth in breast cancer cells (BCC), including hormone-resistant cell models. These effects were associated with cell-cycle arrest and modulation of related proteins (cyclin D1, cyclin E, p27, and p21), all target genes of FoxO3a, an ubiquitous transcription factor negatively regulated by AKT. Lamotrigine also increases the expression of another FoxO3a target, PTEN, which, in turn, downregulates the PI3K/Akt signaling pathway, with consequent dephosphorylation, thus activation, of FoxO3a. Moreover, lamotrigine induces FoxO3a expression by increasing its transcription through FoxO3a recruitment on specific FHRE located on its own promoter, in an autoregulatory fashion. Finally, lamotrigine significantly reduced tumor growth , increasing FoxO3a expression. The anticonvulsant drug lamotrigine shows strong antiproliferative activity on breast cancer, both and Thus, drug repurposing could represent a valuable option for a molecularly targeted therapy in breast cancer patients. .
乳腺癌是一种复杂且异质性的疾病，其独特的组织学特征决定了治疗方法。尽管乳腺癌患者的临床预后已经得到了显著改善，但对常见内分泌和化疗治疗的耐药性仍然是复发和死亡的主要原因。因此，需要努力寻找新的分子来应用于乳腺癌治疗。作为一种“更快”的方法来实现这一目标，我们评估了广泛用于抗癫痫的拉莫三嗪是否可以“重新定位”为乳腺癌的抗肿瘤药物。我们的数据表明，拉莫三嗪抑制了乳腺癌细胞（BCC）的增殖、锚定依赖性和非依赖性细胞生长，包括激素耐药细胞模型。这些作用与细胞周期停滞和相关蛋白（细胞周期蛋白 D1、细胞周期蛋白 E、p27 和 p21）的调节有关，所有这些都是 FoxO3a 的靶基因，FoxO3a 是一种普遍存在的转录因子，受 AKT 负调控。拉莫三嗪还通过增加其自身启动子上特定 FHRE 上的 FoxO3a 募集来增加另一个 FoxO3a 靶标 PTEN 的表达，从而下调 PI3K/Akt 信号通路，导致 FoxO3a 去磷酸化，从而激活。此外，拉莫三嗪通过增加其转录来增加 FoxO3a 的表达，从而以自调控的方式募集 FoxO3a。最后，拉莫三嗪显著降低肿瘤生长，增加 FoxO3a 表达。抗惊厥药物拉莫三嗪对乳腺癌具有很强的抗增殖活性，无论是在体内还是在体外。因此，药物重新定位可能是乳腺癌患者分子靶向治疗的一种有价值的选择。
