Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia School of Medicine, Charlottesville, VA, USA.
Cancer Lett. 2018 Nov 1;436:75-86. doi: 10.1016/j.canlet.2018.08.015. Epub 2018 Aug 16.
Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. Although most patients respond to frontline therapy, virtually all patients relapse with chemoresistant disease. This study addresses the hypothesis that carboplatin or tamoxifen + FTY720, a sphingosine analogue, will minimize or circumvent drug-resistance in ovarian cancer cells and tumor models. In vitro data demonstrate that FTY720 sensitized two drug-resistant (A2780. cp20, HeyA8. MDR) and two high-grade serous ovarian cancer cell lines (COV362, CAOV3) to carboplatin, a standard of care for patients with ovarian cancer, and to the selective estrogen receptor modulator tamoxifen. FTY720 + tamoxifen was synergistic in vitro, and combinations of FTY720 + carboplatin or + tamoxifen were more effective than each single agent in a patient-derived xenograft model of ovarian carcinoma. FTY720 + tamoxifen arrested tumor growth. FTY720 + carboplatin induced tumor regressions, with tumor volumes reduced by ∼86% compared to initial tumor volumes. Anti-tumor efficacy was concomitant with increases in intracellular proapoptotic lipid ceramide. The data suggest that FTY720 + tamoxifen or carboplatin may be effective in treating ovarian tumors.
卵巢癌是美国女性癌症相关死亡的第五大主要原因。尽管大多数患者对一线治疗有反应，但几乎所有患者都会因化疗耐药性疾病而复发。本研究旨在验证以下假设：卡铂或他莫昔芬+FTY720（一种鞘氨醇类似物）将最大限度地减少或规避卵巢癌细胞和肿瘤模型中的耐药性。体外数据表明，FTY720 使两种耐药（A2780.cp20、HeyA8.MDR）和两种高级别浆液性卵巢癌细胞系（COV362、CAOV3）对卡铂（卵巢癌患者的标准治疗药物）和选择性雌激素受体调节剂他莫昔芬敏感。FTY720+他莫昔芬在体外具有协同作用，FTY720+卡铂或+他莫昔芬的组合在卵巢癌患者来源异种移植模型中的疗效优于每种单一药物。FTY720+他莫昔芬抑制肿瘤生长。FTY720+卡铂诱导肿瘤消退，与初始肿瘤体积相比，肿瘤体积减少了约 86%。抗肿瘤疗效与细胞内促凋亡脂质神经酰胺的增加同时发生。数据表明，FTY720+他莫昔芬或卡铂可能对治疗卵巢肿瘤有效。
