Olsen Cathrine Elisabeth, Berg Kristian, Selbo Pål Kristian, Weyergang Anette
Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway.
Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway.
Free Radic Biol Med. 2013 Dec;65:1300-1309. doi: 10.1016/j.freeradbiomed.2013.09.010. Epub 2013 Sep 26.
A wide range of anti-cancer therapies have been shown to induce resistance upon repetitive treatment and such adapted resistance may also cause cross-resistance to other treatment modalities. We here show that MES-SA/Dx5 cells with adapted resistance to doxorubicin (DOX) are cross-resistant to photodynamic therapy (PDT). A DOX-induced increased expression of the reactive oxygen species (ROS)-scavenging proteins glutathione peroxidase (GPx) 1 and GPx4 in MES-SA/Dx5 cells was indicated as the mechanism of resistance to PDT in line with the reduction in PDT-generated ROS observed in this cell line. ROS-induced p38 activation was, in addition, shown to be reduced to one-third of the signal of the parental MES-SA cells 2h after PDT, and addition of the p38 inhibitor SB203580 confirmed p38 activation as a death signal after PDT in the MES-SA cells. The MES-SA/Dx5 cells were also cross-resistant to ionizing radiation in agreement with the increased GPx1 and GPx4 expression. Surprisingly, PDT-induced endo/lysosomal release of the ribosome-inactivating protein gelonin (photochemical internalization (PCI)) was more effective in the PDT-resistant MES-SA/Dx5 cells, as measured by synergy calculations in both cell lines. Analysis of death-inducing signaling indicated a low activation of caspase-3 and a strong PARP I cleavage after PDT and PCI in both cell lines. The PARP I activation was, however, stronger after PCI than after PDT in the MES-SA cells, but not in the MES-SA/Dx5 cells, and therefore cannot explain the strong PCI effect in the MES-SA/Dx5 cells. In conclusion PCI of recombinant gelonin circumvents ROS resistance in an apoptosis-independent manner.
多种抗癌疗法已被证明在重复治疗后会诱导耐药性，而这种适应性耐药也可能导致对其他治疗方式的交叉耐药。我们在此表明，对多柔比星（DOX）具有适应性耐药的MES-SA/Dx5细胞对光动力疗法（PDT）具有交叉耐药性。DOX诱导MES-SA/Dx5细胞中活性氧（ROS）清除蛋白谷胱甘肽过氧化物酶（GPx）1和GPx4的表达增加，这被认为是对PDT耐药的机制，这与该细胞系中观察到的PDT产生的ROS减少一致。此外，在PDT后2小时，ROS诱导的p38激活被证明降至亲本MES-SA细胞信号的三分之一，并且添加p38抑制剂SB203580证实p38激活是MES-SA细胞PDT后的死亡信号。MES-SA/Dx5细胞对电离辐射也具有交叉耐药性，这与GPx1和GPx4表达增加一致。令人惊讶的是，通过两种细胞系的协同计算测量，PDT诱导的核糖体失活蛋白去甲凝胶素的内吞/溶酶体释放（光化学内化（PCI））在对PDT耐药的MES-SA/Dx5细胞中更有效。对死亡诱导信号的分析表明，在两种细胞系中，PDT和PCI后caspase-3的激活较低，而PARP I的切割较强。然而，在MES-SA细胞中，PCI后PARP I的激活比PDT后更强，但在MES-SA/Dx5细胞中并非如此，因此无法解释MES-SA/Dx5细胞中强大的PCI效应。总之，重组去甲凝胶素的PCI以不依赖凋亡的方式规避了ROS耐药性。
