Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan.
Department of Thoracic Surgery, Mackay Memorial Hospital, Taipei 10449, Taiwan.
Cancer Lett. 2015 Aug 10;364(2):125-34. doi: 10.1016/j.canlet.2015.05.006. Epub 2015 May 11.
Triple-negative breast cancer (TNBC) is chemotherapy-refractory and associated with poor clinical prognosis. Doxorubicin (Doxo), a class I anthracycline and first-line anticancer agent, effective against a wide spectrum of neoplasms including breast carcinoma, is associated with several cumulative dose-dependent adverse effects, including cardiomyopathy, typhilitis, and acute myelotoxicity. This study evaluated the usability of Ovatodiolide (Ova) in sensitizing TNBC cells to Doxo cytotoxicity, so as to reduce Doxo effective dose and consequently its adverse effects. TNBC cell lines MDA-MB-231 and HS578T were used. Pre-treatment of the TNBC cells with 10 µM Ova 24 h before Doxo administration increased the Doxo anticancer effect (IC50 1.4 µM) compared to simultaneous treatment with Doxo ( IC50 1.8 µM), or Doxo alone (IC50 9.2 µM). Intracellular accumulation of Doxo was lowest in Ova pre-treated cells at all Doxo concentrations, when compared with Doxo or simultaneously treated cells. In comparison to the Doxo-only group, cell cycle analysis of MDA-MB-231 cells treated concurrently with 2.5 µM Ova and 1.25 µM Doxo showed increased percentage of cells arrested at G0/G1; however, pre-treatment with the same concentration of Ova 24 h before Doxo showed greater tumor growth inhibition, with a 2.4-fold increased percentage of cells in G0/G1 arrest, greater Doxo-induced apoptosis, and significantly reduced intracellular Doxo accumulation. Additionally, Ova-sensitized TNBC cells also lost their cancer stem cell-like phenotype evidenced by significant dissolution, necrosis of formed mammospheres. Taken together, these findings indicate that Ova sensitizes TNBC cells to Doxo and potentiates doxorubicin-induced elimination of the TNBC cancer stem cell-like phenotype.
三阴性乳腺癌（TNBC）是化疗耐药的，且与不良临床预后相关。多柔比星（Doxo），一种 I 型蒽环类药物和一线抗癌药物，对包括乳腺癌在内的多种肿瘤具有广泛的疗效，但其与多种累积剂量依赖性的不良反应相关，包括心肌病、肠炎和急性骨髓毒性。本研究评估了卵形菌内酯（Ova）在增强 TNBC 细胞对 Doxo 细胞毒性敏感性方面的可用性，从而降低 Doxo 的有效剂量，减少其不良反应。本研究使用了 TNBC 细胞系 MDA-MB-231 和 HS578T。与 Doxo 同时处理（IC50 为 1.8 µM）或单独 Doxo 处理（IC50 为 9.2 µM）相比，在给予 Doxo 前 24 小时用 10 µM Ova 预处理 TNBC 细胞可增强 Doxo 的抗癌效果（IC50 为 1.4 µM）。与 Doxo 或同时处理的细胞相比，在所有 Doxo 浓度下，用 Ova 预处理的细胞内 Doxo 的积累最低。与单独 Doxo 组相比，同时用 2.5 µM Ova 和 1.25 µM Doxo 处理的 MDA-MB-231 细胞的细胞周期分析显示，G0/G1 期的细胞比例增加；然而，用相同浓度的 Ova 预处理 24 小时后，Doxo 的肿瘤生长抑制作用更大，G0/G1 期的细胞比例增加了 2.4 倍，Doxo 诱导的细胞凋亡增加，细胞内 Doxo 的积累显著减少。此外，Ova 增敏的 TNBC 细胞也失去了它们的癌症干细胞样表型，形成的乳腺球体显著溶解和坏死。综上所述，这些发现表明 Ova 增敏 TNBC 细胞对 Doxo 的敏感性，并增强 Doxo 诱导的 TNBC 癌症干细胞样表型的消除。
