Taxane-based therapy provides a survival benefit in patients with metastatic prostate cancer, yet the median survival is less than 20 months in this setting due in part to taxane-associated resistance. Innovative strategies are required to overcome chemoresistance for improved patient survival. Here, NanoOrl, a new experimental nanoparticle formulation of the FDA-approved drug, orlistat, was investigated for its cytotoxicity in taxane-resistant prostate cancer utilizing two established taxane-resistant (TxR) cell lines. Orlistat is a weight loss drug that inhibits gastric lipases, but is also a potent inhibitor of fatty acid synthase (FASN), which is overexpressed in many types of cancer. NanoOrl was also investigated for its potential to synergize with taxanes in TxR cell lines. Both orlistat and NanoOrl synergistically inhibited cell viability when combined with paclitaxel, docetaxel, and cabazitaxel in PC3-TxR and DU145-TxR cells, yet these combinations were also additive in parental lines. We observed synergistic levels of apoptosis in TxR cells treated with NanoOrl and docetaxel in combination. Mechanistically, the synergy between orlistat and taxanes was independent of effects on the P-glycoprotein multidrug resistance protein, as determined by an efflux activity assay. On the other hand, immunoblot and immunofluorescence staining with an anti-detyrosinated tubulin antibody demonstrated that enhanced microtubule stability was induced by combined NanoOrl and docetaxel treatment in TxR cells. Furthermore, TxR cells exhibited higher lipid synthesis, as demonstrated by 14C-choline incorporation that was abrogated by NanoOrl. These results provide a strong rationale to assess the translational potential of NanoOrl to overcome taxane resistance. Mol Cancer Ther; 16(9); 1819–30. ©2017 AACR .

中文翻译：

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含奥利司他的纳米粒子和紫杉烷类的联合治疗具有协同作用，并增强了抗紫杉烷类前列腺癌细胞的微管稳定性。

紫杉烷类疗法可为转移性前列腺癌患者提供生存优势，但在这种情况下，中位生存期不到20个月，部分原因是紫杉烷相关的耐药性。需要创新的策略来克服化学耐药性，以提高患者的生存率。在这里，使用两种已建立的紫杉烷抗性（TxR）细胞系，研究了FDA批准的药物orlistat的新实验纳米颗粒制剂NanoOrl在紫杉烷抗性前列腺癌中的细胞毒性。奥利司他（Orlistat）是一种减肥药物，可抑制胃脂肪酶，但还是有效的脂肪酸合酶（FASN）抑制剂，在许多类型的癌症中均过表达。还研究了NanoOrl与TxR细胞系中紫杉烷类药物协同作用的潜力。当在PC3-TxR和DU145-TxR细胞中与紫杉醇，多西紫杉醇和卡巴他赛合用时，奥利司他和NanoOrl均协同抑制细胞活力，但这些组合在亲本系中也是加性的。我们观察到用NanoOrl和多西他赛联合处理的TxR细胞凋亡的协同水平。从机理上讲，奥利司他和紫杉烷类之间的协同作用独立于对P-糖蛋白多药耐药蛋白的影响，如通过外排活性测定所确定的。另一方面，用抗脱酪氨酸微管蛋白抗体进行的免疫印迹和免疫荧光染色证明，结合NanoOrl和多西他赛治疗TxR细胞可诱导增强的微管稳定性。此外，TxR细胞表现出更高的脂质合成，如NanoOrl废除的14C-胆碱掺入所证明的。这些结果为评估NanoOrl克服紫杉烷抗性的翻译潜力提供了强有力的依据。分子癌疗法；16（9）; 1819–30。©2017 AACR。