Aouad Patrick, Saikali Melody, Abdel-Samad Rana, Fostok Sabreen, El-Houjeiri Leeanna, Pisano Claudio, Talhouk Rabih, Darwiche Nadine
Departments of aBiology bBiochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon cMedicinal Investigational Research, BIOGEM, Ariano Irpino, Italy.
Anticancer Drugs. 2017 Aug;28(7):757-770. doi: 10.1097/CAD.0000000000000511.
Despite recent advances in chemotherapy, aggressive and metastatic breast cancers remain refractory to targeted therapy and the development of novel drugs is urgently needed. Retinoids are crucial regulators of cellular proliferation, differentiation, and cell death, and have shown potent chemotherapeutic and chemopreventive properties. The major drawback of the use of all-trans retinoic acid (ATRA) in cancer therapy is disease relapse. Therefore, synthetic retinoids, specifically ST1926, have emerged as potent anticancer agents. Given the importance of the microenvironment in modulating the response of cancer cells to chemotherapeutic drugs, we investigated the antitumor activities of ST1926 in two-dimensional (2D) and different three-dimensional (3D) human breast cancer models and compared them with ATRA. We have shown that in 2D cell culture models, ATRA-resistant MCF-7 and MDA-MB-231 cells were sensitive to ST1926 at submicromolar concentrations that spared the 'normal-like' breast epithelial cells. ST1926 induced apoptosis and S-phase arrest, caused DNA damage, and downregulated the Wnt/β-catenin pathway in breast cancer cells in 2D and 3D cell culture models. ST1926-mediated growth inhibition was independent of the retinoid receptor-signaling pathway. Long-term treatments with low submicromolar ST1926 concentrations reduced the anchorage-independent growth and decreased the sphere-forming ability of breast cancer progenitor cells in the sphere formation assay. Furthermore, ST1926 potently induced cell death of breast cancer cells under 3D conditions and spared the lumen-forming ability of normal-like breast epithelial cells. In tested 3D models, ATRA had minimal effects on the growth of breast cancer cells compared with ST1926. In summary, our results highlight the therapeutic potential of ST1926 in breast cancer and warrant its further clinical development.
尽管化疗最近取得了进展，但侵袭性和转移性乳腺癌对靶向治疗仍然难治，因此迫切需要开发新型药物。维甲酸是细胞增殖、分化和细胞死亡的关键调节因子，并已显示出强大的化疗和化学预防特性。全反式维甲酸（ATRA）用于癌症治疗的主要缺点是疾病复发。因此，合成维甲酸，特别是ST1926，已成为有效的抗癌药物。鉴于微环境在调节癌细胞对化疗药物反应中的重要性，我们研究了ST1926在二维（2D）和不同三维（3D）人乳腺癌模型中的抗肿瘤活性，并将其与ATRA进行了比较。我们已经表明，在2D细胞培养模型中，对ATRA耐药的MCF-7和MDA-MB-231细胞在亚微摩尔浓度下对ST1926敏感，而该浓度对“类正常”乳腺上皮细胞没有影响。在2D和3D细胞培养模型中，ST1926诱导乳腺癌细胞凋亡和S期阻滞，导致DNA损伤，并下调Wnt/β-连环蛋白通路。ST1926介导的生长抑制独立于维甲酸受体信号通路。在成球试验中，用低亚微摩尔浓度的ST1926进行长期处理可降低乳腺癌祖细胞的非锚定依赖性生长并降低其成球能力。此外，ST1926在3D条件下能有效诱导乳腺癌细胞死亡，而不影响类正常乳腺上皮细胞形成管腔的能力。在测试的3D模型中，与ST1926相比，ATRA对乳腺癌细胞生长的影响最小。总之，我们的结果突出了ST1926在乳腺癌中的治疗潜力，值得进一步开展临床研究。
