Marazzi L, Parodi M T, Di Martino D, Ferrari S, Tonini G P
Department of Haematology and Oncology, G. Gaslini Children's Hospital, Genova, Italy.
Anticancer Res. 1991 Mar-Apr;11(2):947-52.
Erythroid cell differentiation can be achieved in vitro by means of several chemical or natural agents. Cell differentiation is accompanied by biochemical and molecular changes which show that the inducer is active at different molecular levels. Among the chemical agents that are able to induce cell differentiation, the anticancer drugs are of great interest for the emerging study of in vitro and in vivo models for differentiation treatment. Cis-diamminedichloroplatinum II (CDDP), a crosslinking DNA compound, is usually employed at a high dosage in treating solid tumors. We have demonstrated that CDDP was also able to induce K562 cells towards erythroid differentiation. In our experiment 2.5 micrograms/ml of CDDP caused expression of alpha-globin chain gene and production of haemoglobulin. Continuous presence of the drug was not necessary to induce the cell to produce haemoglobin. Five days after CDDP treatment, the expression of c-myc oncogene had risen, while H3 histone mRNA expression fell to undetectable levels within 24 hours. Transferrin (Tf) receptor mRNA was reduced but later (about 48 hours) than c-myc and H3 messenger RNAs. The inhibition of cell proliferation was correlated both with the reduced expression of Tf receptor mRNA and low expression of the protein. However, expression of the cytoskeleton vimentin gene was only slightly affected during the time-course of the experiment. Data show that at least three phases were present in the irreversible CDDP induction of haemoglobin synthesis in the K562 cell. The erythroid differentiation was first preceded by a rise of c-myc mRNA, which probably precommits the cell towards the erythroid lineage. The mRNA levels of the cell-cycle dependent genes, H3 and Tf receptor, decreased and inhibition of DNA synthesis and loss of cell proliferation were detected. Finally, the alpha-globin chain gene was actively transcribed and the cell produced haemoglobin.
通过几种化学或天然试剂可在体外实现红细胞系细胞分化。细胞分化伴随着生化和分子变化，这表明诱导剂在不同分子水平上具有活性。在能够诱导细胞分化的化学试剂中，抗癌药物对于新兴的体外和体内分化治疗模型研究具有重要意义。顺二氯二氨铂（II）（CDDP），一种交联DNA化合物，通常以高剂量用于治疗实体瘤。我们已经证明，CDDP也能够诱导K562细胞向红细胞系分化。在我们的实验中，2.5微克/毫升的CDDP导致α-珠蛋白链基因表达和血红蛋白生成。诱导细胞产生血红蛋白并不需要药物持续存在。CDDP处理五天后，c-myc癌基因的表达升高，而H3组蛋白mRNA表达在24小时内降至无法检测的水平。转铁蛋白（Tf）受体mRNA减少，但比c-myc和H3信使RNA晚（约48小时）。细胞增殖的抑制与Tf受体mRNA表达降低和蛋白质低表达均相关。然而，在实验过程中，细胞骨架波形蛋白基因的表达仅受到轻微影响。数据表明，K562细胞中CDDP诱导血红蛋白合成的不可逆过程至少存在三个阶段。红细胞系分化首先是c-myc mRNA升高，这可能使细胞预先定向于红细胞系。细胞周期依赖性基因H3和Tf受体的mRNA水平下降，检测到DNA合成抑制和细胞增殖丧失。最后，α-珠蛋白链基因被积极转录，细胞产生血红蛋白。
