N,C偶联萘异喹啉生物碱ancistrocladinium A属于一类具有强抗原生虫活性的新型天然产物。然而，它对肿瘤细胞的影响尚未被探究。我们证明了ancistrocladinium A在多发性骨髓瘤（MM）中的抗肿瘤活性，这是一种目前无法治愈的血液癌症，代表了适应蛋白毒性应激的模型疾病。活力实验显示，ancistrocladinium A对MM细胞系，包括对蛋白酶抑制剂（PI）耐药性的细胞系和原代MM细胞，具有强大的诱导凋亡作用，但对非恶性血液细胞没有影响。与PI卡菲索酮或组蛋白去乙酰化酶抑制剂泛波诺斯塔特的同时治疗可明显增强ancistrocladinium A诱导的凋亡效应。生物素化的ancistrocladinium A质谱分析显示，RNA剪接相关蛋白明显富集。受影响的RNA剪接相关通路包括参与蛋白毒性应激反应的基因，如PSMB5相关基因和热休克蛋白HSP90和HSP70。此外，我们发现ATF4和ATM/H2AX通路的明显诱导，这两个通路在蛋白毒性和氧化应激后的细胞整合性反应中起关键作用。综上所述，我们的数据表明，ancistrocladinium A靶向调节MM细胞的应激调控，并改善对PI的治疗反应或克服PI耐药性，因此可能是一种有前景的潜在治疗药物。

The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.