Brook Emma M, Helem Shaya J, McDonald Charlotte C M, Magon Nicholas J, Selwood Andrew I, Harwood D Tim, Jaiswal Jagdish K, Hampton Mark B, Dachs Gabi U
Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, 8011, New Zealand.
Mātai Hāora - Centre for Redox Biology and Medicine, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand.
Med Oncol. 2025 Jun 23;42(7):278. doi: 10.1007/s12032-025-02826-x.
Portimine is a marine cyclic imine toxin produced by the dinoflagellate Vulcanodinium rugosum. This compound has potent apoptotic activity against cancer cells in culture. However, despite the high cytotoxicity of portimine in vitro, it has low toxicity in vivo in comparison to related cyclic imine compounds. It was hypothesised that metabolism of portimine contributed to its reduced toxicity.
Cytotoxicity of portimine A was assessed in four murine and one human cancer cell line. In vitro metabolism of portimine was performed in liver S9 fractions and microsomes from human and mouse, with paclitaxel as control, and in the lysates of cultured cells. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to measure the concentrations of portimine in the biological samples.
The concentration of portimine that reduced cell viability by 50% ranged from 2.0 to 2.6 nM. LC-MS/MS analysis found insignificant losses of portimine in mouse or human liver fractions or cell lysates. There was also no reduction in bioactivity when these biological samples containing portimine were added to cancer cell lines.
The data showed that exposure to cellular metabolism did not lead to significant loss of portimine bioactivity. This is valuable information for the development of portimine as a therapeutic agent, but it does not explain the limited in vivo toxicity in comparison to other cyclic imines.
波替米星是一种由海洋甲藻粗糙火神藻产生的海洋环状亚胺毒素。该化合物在体外培养中对癌细胞具有强大的凋亡活性。然而，尽管波替米星在体外具有高细胞毒性，但与相关环状亚胺化合物相比，其在体内的毒性较低。据推测，波替米星的代谢导致其毒性降低。
在四种小鼠癌细胞系和一种人类癌细胞系中评估波替米星A的细胞毒性。以紫杉醇作为对照，在人及小鼠的肝脏S9组分和微粒体以及培养细胞的裂解物中进行波替米星的体外代谢研究。采用液相色谱串联质谱法（LC-MS/MS）测定生物样品中波替米星的浓度。
使细胞活力降低50%的波替米星浓度范围为2.0至2.6 nM。LC-MS/MS分析发现，在小鼠或人类肝脏组分或细胞裂解物中，波替米星的损失不显著。当将这些含有波替米星的生物样品添加到癌细胞系中时，其生物活性也没有降低。
数据表明，暴露于细胞代谢过程中并未导致波替米星生物活性的显著丧失。这对于将波替米星开发为治疗剂而言是有价值的信息，但它并不能解释与其他环状亚胺相比其体内毒性有限的原因。
