Background: Over the last few decades of treatment, the outcomes for at least some subsets of neuroendocrine neoplasms (NENs) have improved. However, the identification of new vulnerabilities for this heterogeneous group of cancers remains a priority. Methods: Using two libraries of compounds selected for potential repurposing, we identified the inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylases (HDAC) as the agents with the highest activity. We validated the hits in an expanded set of neuroendocrine cell lines and examined the mechanisms of action. Results: In Kelly, NH-6, and NCI-H82, which are two neuroblastoma and one small cell lung cancer cell lines, respectively, metabolic studies suggested that cell death following NAMPT inhibition is the result of a reduction in basal oxidative phosphorylation and energy production. NAMPT is the rate-limiting enzyme in the production of NAD+, and in the three cell lines, NAMPT inhibition led to a marked reduction in the ATP and NAD+ levels and the catalytic activity of the citric acid cycle. Moreover, comparative analysis of the mRNA expression in drug-sensitive and -insensitive cell lines found less dependency of the latter on oxidative phosphorylation for their energy requirement. Further, the analysis of HDAC and NAMPT inhibitors administered in combination found marked activity using low sub-lethal concentrations of both agents, suggesting a synergistic effect. Conclusion: These data suggest NAMPT inhibitors alone or in combination with HDAC inhibitors could be particularly effective in the treatment of neuroendocrine neoplasms.
背景：在最近几十年的治疗中，神经内分泌肿瘤（NENs）至少部分亚型的预后有所改善。然而，针对这一异质性癌症群体寻找新的治疗靶点仍是当务之急。方法：通过筛选两个具有潜在再利用价值的化合物库，我们发现烟酰胺磷酸核糖转移酶（NAMPT）抑制剂和组蛋白去乙酰化酶（HDAC）抑制剂具有最强的抗肿瘤活性。我们在扩展的神经内分泌细胞系中验证了这些候选药物，并探究了其作用机制。结果：在两种神经母细胞瘤细胞系（Kelly和NH-6）及一种小细胞肺癌细胞系（NCI-H82）中，代谢研究表明NAMPT抑制引发的细胞死亡源于基础氧化磷酸化及能量生成的减少。NAMPT是NAD+合成的限速酶，在这三种细胞系中，抑制NAMPT导致ATP和NAD+水平显著降低，并抑制了三羧酸循环的催化活性。此外，通过对药物敏感与不敏感细胞系的mRNA表达进行比较分析，发现后者对氧化磷酸化供能的依赖性较低。进一步研究发现，联合使用HDAC与NAMPT抑制剂时，即使两者均采用低于致死浓度的剂量，仍能产生显著的抗肿瘤活性，提示存在协同效应。结论：这些数据表明，NAMPT抑制剂单独使用或与HDAC抑制剂联合使用，可能对神经内分泌肿瘤的治疗具有特殊疗效。
Novel Therapeutic Strategies Exploiting the Unique Properties of Neuroendocrine Neoplasms
肿瘤(癌症)患者之家