Background:Docetaxel (Doc) resistance in prostate cancer (CaP) patients is associated with the secretion of proinflammatory cytokines that induce an interaction between tumor cells and macrophages. Tumor cell-derived cytokines released in response to increased intracellular concentrations of Doc attract monocytes and macrophages to the tumor site and induce Doc resistance.Objectives:To generate Doc-resistant CaP cell line LNCaP-Doc/R and determine if we could modulate/reduce proinflammatory signals by administering Doc, encapsulated in a PLGA: Chitosan core-shell hierarchical nanoparticle (HNP-Doc) in the resistant and naive CaP Cells.Methods:LNCaP-Doc/R cells were generated by intermittent increasing concentration of Doc, proliferation, growth curve and cytotoxicity of Doc and HNP-Doc were evaluated followed by LNCaP and LNCaP-Doc/R (Doc resistant) CaP cells co-cultured with U937 monocytes with either free Doc or HNP-Doc encapsulated Doc, and various cytokine levels were measured in the conditioned media to assess the cytokine levels.Results:Our results show that LNCaP-Doc-R cells had slower growth in the lag phase, needed a 90-fold increase in Doc concentration to achieve 50% killing. Basal levels of cytokines secreted by LNCaP and LNCaP-Doc/R cells in response to free Doc and HNP-encapsulated Doc differed considerably, with free Doc-treated cells demonstrating, on average, 2–7-fold higher pro-inflammatory cytokine levels as compared to HNP-encapsulated Doc. The levels of pro-inflammatory cytokines, such as IFNγ, IL-1α, and RANTES, were increased ~2.38, ~2.75, and ~5.75-fold, respectively, in free Doc-treated CaP cells and were significantly lower when Doc was delivered via HNP. Further, LNCaP-Doc/R cells co-cultured with U937 had significantly lower markers of macrophage differentiation in response to HNP-encapsulated Doc treatment as opposed to free Doc treatment.Conclusions:Based on this analysis, we conclude that Doc treatment in vitro is associated with a proinflammatory response involving cytokines linked to macrophage recruitment and activation, with a lesser proinflammatory response with HNP-encapsulated Doc treatment.
背景：前列腺癌患者对多西他赛的耐药性与促炎细胞因子的分泌相关，这些因子诱导肿瘤细胞与巨噬细胞间的相互作用。肿瘤细胞在细胞内多西他赛浓度升高时释放的细胞因子会吸引单核细胞和巨噬细胞至肿瘤部位，并诱导多西他赛耐药。 目的：建立多西他赛耐药的前列腺癌细胞系LNCaP-Doc/R，并探究通过使用包裹于PLGA:壳聚糖核壳结构分级纳米颗粒中的多西他赛（HNP-Doc）对耐药及初治前列腺癌细胞进行给药，能否调节或降低促炎信号。 方法：通过间歇性递增多西他赛浓度构建LNCaP-Doc/R细胞系，评估其增殖特性、生长曲线及对多西他赛与HNP-Doc的细胞毒性。随后将LNCaP与LNCaP-Doc/R（多西他赛耐药）前列腺癌细胞与U937单核细胞共培养，分别使用游离多西他赛或HNP-Doc包裹的多西他赛处理，通过检测条件培养基中多种细胞因子水平评估细胞因子表达变化。 结果：研究显示LNCaP-Doc/R细胞在滞后期生长更缓慢，需将多西他赛浓度提升90倍才能达到50%的杀伤效果。LNCaP与LNCaP-Doc/R细胞对游离多西他赛和HNP包裹多西他赛的基础细胞因子分泌水平存在显著差异：游离多西他赛处理的细胞促炎细胞因子水平平均比HNP包裹多西他赛处理组高2-7倍。具体而言，游离多西他赛处理的前列腺癌细胞中IFNγ、IL-1α和RANTES等促炎细胞因子水平分别升高约2.38倍、2.75倍和5.75倍，而通过HNP递送多西他赛时这些因子水平显著降低。此外，与游离多西他赛处理相比，HNP包裹多西他赛处理的LNCaP-Doc/R与U937共培养体系中巨噬细胞分化标志物表达显著降低。 结论：本研究表明体外多西他赛治疗会引发涉及巨噬细胞募集与活化相关细胞因子的促炎反应，而HNP包裹多西他赛治疗产生的促炎反应较弱。
肿瘤(癌症)患者之家