Honma Y, Okabe-Kado J, Hozumi M, Uehara Y, Mizuno S
Department of Chemotherapy, Saitama Cancer Center Research Institute, Japan.
Cancer Res. 1989 Jan 15;49(2):331-4.
Herbimycin A, a benzoquinonoid ansamycin antibiotic, is found to reduce intracellular phosphorylation by tyrosine protein kinase. The human chronic myelogenous leukemia cell line K562 expresses a structurally altered c-abl protein with tyrosine kinase activity. When K562 cells are induced to undergo erythroid differentiation by hemin, reduction in the intracellular level of tyrosine phosphorylation occurs. In order to understand the relationship between induction of differentiation and reduction of tyrosine phosphorylation by the c-abl gene product, the effect that herbimycin A, a selective inhibitor of intracellular tyrosine kinase activity, exerts on the differentiation of K562 cells was examined. Reduction of tyrosine phosphorylation in K562 cells by herbimycin A was observed within 1 h. Noncytotoxic concentrations of herbimycin A induced erythroid differentiation of K562 cells but not of murine erythroleukemia 745A cells. The other human myeloid leukemia cell lines (HL-60, THP-1, and U937) tested were not induced to undergo cell differentiation by this antibiotic. Herbimycin A and the other well-known inducers such as hemin, butyric acid, Adriamycin, and 1-beta-D-arabinofuranosylcytosine had additive or more than additive effects on induction of erythroid differentiation of K562 cells. With respect to inhibition of cell growth, the sensitivity of K562 cells to herbimycin A was highest in the human leukemia cell lines we tested. Noncytotoxic concentrations of herbimycin enhanced the antiproliferative effect of Adriamycin or 1-beta-D-arabinofuranosylcytosine on K562 cells. Combination therapy with herbimycin A and its derivatives may be considered for use in the treatment of some types of leukemia where tyrosine kinase activities are implicated as determinants of the oncogenic state.
赫比霉素A是一种苯醌类安莎霉素抗生素，它能降低酪氨酸蛋白激酶引起的细胞内磷酸化作用。人类慢性粒细胞白血病细胞系K562表达一种具有酪氨酸激酶活性的结构改变的c-abl蛋白。当用氯化血红素诱导K562细胞进行红系分化时，细胞内酪氨酸磷酸化水平会降低。为了了解分化诱导与c-abl基因产物酪氨酸磷酸化减少之间的关系，研究了细胞内酪氨酸激酶活性的选择性抑制剂赫比霉素A对K562细胞分化的影响。在1小时内观察到赫比霉素A使K562细胞中的酪氨酸磷酸化减少。非细胞毒性浓度的赫比霉素A诱导K562细胞发生红系分化，但不诱导鼠红白血病745A细胞分化。所测试的其他人类髓系白血病细胞系（HL-60、THP-1和U937）未被这种抗生素诱导发生细胞分化。赫比霉素A与其他知名诱导剂如氯化血红素、丁酸、阿霉素和1-β-D-阿拉伯呋喃糖基胞嘧啶对K562细胞红系分化的诱导具有相加或超相加作用。关于细胞生长抑制，在我们测试的人类白血病细胞系中，K562细胞对赫比霉素A的敏感性最高。非细胞毒性浓度的赫比霉素增强了阿霉素或1-β-D-阿拉伯呋喃糖基胞嘧啶对K562细胞的抗增殖作用。对于某些酪氨酸激酶活性被认为是致癌状态决定因素的白血病类型，可考虑使用赫比霉素A及其衍生物进行联合治疗。
