IRCCS AOU San Martino Polyclinic Hospital, 16132 Genova, Italy.
Department of Experimental Medicine (DIMES), University of Genova, 16126 Genova, Italy.
Molecules. 2020 Nov 10;25(22):5234. doi: 10.3390/molecules25225234.
Despite significant improvement of neuroblastoma (NB) patients' survival due to recent treatment advancements in recent years, NB is still associated with high mortality rate. In search of novel strategies to increase NB's susceptibility to pharmacological treatments, we investigated the in vitro and in vivo effects of fendiline hydrochloride as an enhancer of cisplatin antitumor activity. To assess the modulation of fendiline treatment on cisplatin responses, we used in vitro (evaluating NB cell proliferation by XCELLigence technology and colony formation, and gene expression by RT-PCR) and in vivo (NB cell grafts in NOD-SCID mice) models of NB. NB cell treatment with fendiline induced the expression of the ncRNA NDM29, leading to cell differentiation and to the reduction of the expression of MDRs/ABC transporters linked to multidrug resistance. These events were correlated to higher NB cell susceptibility to cisplatin and, consequently, increased its cytotoxic potency. In vivo, this drug interaction causes an enhanced ability of cisplatin to induce apoptosis in NB masses, resulting in tumor growth reduction and prolonged animal survival rate. Thus, the administration of fendiline might be a possible novel therapeutic approach to increase cisplatin efficacy in aggressive and poorly responsive NB cases.
尽管近年来治疗进展显著提高了神经母细胞瘤（NB）患者的生存率，但 NB 仍然与高死亡率相关。为了寻找增加 NB 对药物治疗敏感性的新策略，我们研究了盐酸芬地林作为顺铂抗肿瘤活性增强剂的体外和体内作用。为了评估芬地林治疗对顺铂反应的调节作用，我们使用了 NB 的体外（通过 XCELLigence 技术评估 NB 细胞增殖和集落形成，以及通过 RT-PCR 评估基因表达）和体内（NB 细胞移植到 NOD-SCID 小鼠中）模型。NB 细胞用芬地林处理后，诱导 ncRNA NDM29 的表达，导致细胞分化，并降低与多药耐药相关的 MDRs/ABC 转运体的表达。这些事件与 NB 细胞对顺铂的敏感性增加相关，从而增强了其细胞毒性。在体内，这种药物相互作用导致顺铂在 NB 肿块中诱导细胞凋亡的能力增强，从而减少肿瘤生长并延长动物的存活率。因此，芬地林的给药可能是一种增加顺铂在侵袭性和反应不佳的 NB 病例中疗效的新的治疗方法。
