National Center for Drug Research and Evaluation, National Institute of Health, Rome 00161, Italy.
National Center for Drug Research and Evaluation, National Institute of Health, Rome 00161, Italy.
Toxicol In Vitro. 2020 Jun;65:104819. doi: 10.1016/j.tiv.2020.104819. Epub 2020 Mar 2.
Search for natural substances in association with conventional chemotherapeutic drugs with a chemiosensitizing action easily accessible to the tumor mass has encouraged our studies on voacamine (VOA) and its monomeric units, voacangine and vobasine. Our previous results showed that VOA sensitized multidrug resistant (MDR) osteosarcoma cells (U-2 OS/DX) to doxorubicin (DOX) cytotoxicity. VOA, extracted by Peschiera fuchsiaefolia plant, is a bisindole alkaloid consisting of an Iboga skeleton (voacangine) directly linked to a 2-acyl indole unit (vobasine). High-performance thin-layer chromatography densitometry demonstrated the purity of VOA, voacangine and vobasine samples. Flow cytometry analysis showed that VOA, voacangine and vobasine enhanced DOX accumulation of U-2 OS/DX cells, in equally way, whereas VOA reduced more efficiently DOX efflux. Optical microscopy and clonogenic assay confirmed that VOA was more effective than voacangine and vobasine in enhancing DOX cytotoxic effect. These results showed that monomers linked together are necessary to modulate resistant phenotype of osteosarcoma cells. To complete the study, we evaluated the effect of three compounds on microtubules by confocal microscopy, suggesting that only the whole molecule depolymerizes the microtubules blocking so DOX efflux-mediated by vesicles.
寻找与常规化疗药物联合具有化学增敏作用的天然物质，这些物质容易到达肿瘤部位，这促使我们对蝙蝠葛碱（VOA）及其单体单元蝙蝠葛苏林碱和蝙蝠葛新林碱进行了研究。我们之前的研究结果表明，VOA 增敏多药耐药（MDR）骨肉瘤细胞（U-2 OS/DX）对阿霉素（DOX）的细胞毒性。从 Peschiera fuchsiaefolia 植物中提取的 VOA 是一种双吲哚生物碱，由 Iboga 骨架（蝙蝠葛苏林碱）直接连接到 2-酰基吲哚单元（蝙蝠葛新林碱）组成。高效薄层色谱密度法证明了 VOA、蝙蝠葛苏林碱和蝙蝠葛新林碱样品的纯度。流式细胞术分析表明，VOA、蝙蝠葛苏林碱和蝙蝠葛新林碱以相同的方式增强 U-2 OS/DX 细胞对 DOX 的蓄积，而 VOA 更有效地减少 DOX 的外排。光学显微镜和集落形成实验证实，VOA 比蝙蝠葛苏林碱和蝙蝠葛新林碱更有效地增强 DOX 的细胞毒性作用。这些结果表明，连接在一起的单体是调节骨肉瘤细胞耐药表型所必需的。为了完成这项研究，我们通过共聚焦显微镜评估了这三种化合物对微管的影响，结果表明只有整个分子才能解聚微管，从而阻止囊泡介导的 DOX 外排。
