Ippoliti R, Ginobbi P, Lendaro E, D'Agostino I, Ombres D, Benedetti P A, Brunori M, Citro G
Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biochemical Sciences A. Rossi-Fanelli, University of Rome La Sapienza, Italy.
Cell Mol Life Sci. 1998 Aug;54(8):866-75. doi: 10.1007/s000180050214.
The toxicity of two conjugates containing ribosome-inactivating proteins (RIPs, i.e. saporin and ricin-A chain x-linked to transferrin) has been measured on a prostatic cancer line (PC3) naturally overexpressing the transferrin receptor, in the presence of monensin and chloroquine. This paper investigates whether the increased toxicity of Tf-RIPs induced by monensin and chloroquine may be due to alterations of the normal endocytotic pathway of the complexes mediated by the transferrin receptor. Monensin, besides inducing alkalinization of normally acid intracellular compartments, causes an accumulation of the receptor-bound Tf-RIP in a perinuclear region contiguous to the cisternae of the trans-Golgi network. Chloroquine, though increasing the intracellular pH, seems not to modify the endocytotic pathway of these chimeric molecules. We believe that the enhanced toxicity of the Tf-RIPs may be related to intracellular alkalinization (i.e., endosomal or lysosomal pH) rather than to the effects on the recycling of transferrin receptor-bound toxins. We conclude that the efficacy of chimeric toxins may be modulated not only by the carrier used for their engineering but also by addition of drugs able to influence the stability and activation of the toxins inside the cell.
在莫能菌素和氯喹存在的情况下，已在天然过表达转铁蛋白受体的前列腺癌细胞系（PC3）上测定了两种含有核糖体失活蛋白（RIPs，即与转铁蛋白x连锁的皂草素和蓖麻毒素A链）的缀合物的毒性。本文研究了莫能菌素和氯喹诱导的Tf-RIPs毒性增加是否可能归因于转铁蛋白受体介导的复合物正常内吞途径的改变。莫能菌素除了诱导正常酸性细胞内区室的碱化外，还会使受体结合的Tf-RIP在与反式高尔基体网络池相邻的核周区域积累。氯喹虽然会提高细胞内pH值，但似乎不会改变这些嵌合分子的内吞途径。我们认为Tf-RIPs毒性增强可能与细胞内碱化（即内体或溶酶体pH值）有关，而不是与对转铁蛋白受体结合毒素再循环的影响有关。我们得出结论，嵌合毒素的疗效不仅可以通过用于其工程改造的载体来调节，还可以通过添加能够影响毒素在细胞内稳定性和激活的药物来调节。
