Lopes Miguel Angelo, Meisel Andreas, Dirnagl Ulrich, Carvalho Félix Dias, Bastos Maria de Lourdes
REQUIMTE, Toxicology Department, Faculty of Pharmacy, University of Porto, Portugal.
Neurotoxicology. 2008 Mar;29(2):286-93. doi: 10.1016/j.neuro.2007.12.003. Epub 2007 Dec 31.
Doxorubicin (DOX) is an anthracycline anticancer drug considered to be a first line choice in the treatment of breast cancer, childhood solid tumours, soft tissue sarcomas and aggressive lymphomas. Notwithstanding the fact that DOX does not cross the blood-brain barrier, several modified delivery systems have been recently developed to circumvent this obstacle and use DOX as an effective agent against brain tumours. However, the putative effect of DOX at the CNS remains elusive. Thus, the aim of this work was to investigate and characterise the mode of cell death induced by the anticancer agent DOX in cortical neurons. The obtained results indicated that DOX is neurotoxic to serum-free cultures of cortical neurons in a biphasic concentration manner: for concentrations up to 0.5microM, cell death follows an apoptotic pattern, while for higher concentrations apoptosis is inhibited and necrosis becomes dominant. Apoptosis induced by DOX in our model can occur via different pathways. It is expected that the obtained information from this work can provide new clues about the mechanisms of DOX neurotoxicity that may be of great value for preventing its effects in non-target cells.
多柔比星（DOX）是一种蒽环类抗癌药物，被认为是治疗乳腺癌、儿童实体瘤、软组织肉瘤和侵袭性淋巴瘤的一线选择。尽管DOX不能穿过血脑屏障，但最近已经开发了几种改良的给药系统来克服这一障碍，并将DOX用作对抗脑肿瘤的有效药物。然而，DOX在中枢神经系统的假定作用仍然难以捉摸。因此，这项工作的目的是研究和表征抗癌药物DOX在皮质神经元中诱导的细胞死亡模式。获得的结果表明，DOX对无血清培养的皮质神经元具有双相浓度依赖性神经毒性：对于浓度高达0.5微摩尔的情况，细胞死亡遵循凋亡模式，而对于更高浓度，凋亡受到抑制，坏死占主导地位。在我们的模型中，DOX诱导的凋亡可以通过不同的途径发生。预计这项工作获得的信息可以为DOX神经毒性机制提供新的线索，这可能对预防其在非靶细胞中的作用具有重要价值。
