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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Tyrphostins that suppress the growth of human papilloma virus 16-immortalized human keratinocytes.
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Tyrphostins that suppress the growth of human papilloma virus 16-immortalized human keratinocytes.

机译：抑制人乳头瘤病毒16永生化人角质形成细胞生长的酪氨酸磷酸化抑制剂。

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摘要

Human papilloma virus 16 (HPV16) is considered to be the causative agent for cervical cancer, which ranks second to breast cancer in women's malignancies. In an attempt to develop drugs that inhibit the malignant transformation of HPV16-immortalized epithelial cells, we examined the effect of tyrphostins on such cells. We examined the effect of tyrphostins from four different families on the growth of HPV16-immortalized human keratinocytes (HF-1) cells. We found that they alter their cell cycle distribution, their morphology, and induce cell death by apoptosis. The effects of tyrphostins on HF-1 cells are different from their effects on normal keratinocytes. Growth suppression by AG555 and AG1478 is accompanied by 30% apoptosis in HF-1 cells, but this is not observed in normal keratinocytes. Tyrphostin treatment produces distinctive morphological changes in HF-1 cells and in normal keratinocytes; however, the culture organization of normal keratinocytes is less disrupted. These differential effects of the tyrphostins on HPV16-immortalized keratinocytes compared with their effects on normal keratinocytes suggests that these compounds are suitable candidates for the treatment of papilloma. Previous and present results indicate that group 1 tyrphostins, which inhibit Cdk2 activation, and group 2 tyrphostins, represented by AG1478, a potent epidermal growth factor receptor kinase inhibitor, induce cell cycle arrest; and, in the case of HF-1 cells, apoptosis and differentiation. Cells accumulate in the G(1) phase of the cell cycle at the expense of S and G(2) + M. These compounds block the growth of normal keratinocytes without inducing apoptosis or differentiation, causing them to accumulate in G(1). AG17, which belongs to group 4, exerts its antiproliferative effect mainly by increasing the fractions of cells in G(1) with a concomitant decrease in the fraction of cells in S and G(2) + M.
机译：人乳头瘤病毒16（HPV16）被认为是宫颈癌的病原体，在女性恶性肿瘤中仅次于乳腺癌。在尝试开发抑制HPV16永生化的上皮细胞恶性转化的药物时，我们检查了酪氨酸蛋白酶抑制剂对此类细胞的作用。我们检查了来自四个不同家族的酪氨酸抑制剂对HPV16永生化人类角质形成细胞（HF-1）细胞生长的影响。我们发现它们会改变细胞周期分布，形态并通过凋亡诱导细胞死亡。 tyrphostin对HF-1细胞的作用不同于对正常角质形成细胞的作用。 AG555和AG1478抑制生长的同时，在HF-1细胞中出现30％的细胞凋亡，但在正常的角质形成细胞中未观察到。酪蛋白抑制剂处理可在HF-1细胞和正常角质形成细胞中产生独特的形态变化。但是，正常角质形成细胞的培养组织受到的干扰较小。与它们对正常角质形成细胞的作用相比，酪氨酸蛋白酶抑制剂对HPV16永生化角质形成细胞的这些不同作用表明这些化合物是治疗乳头状瘤的合适候选物。既往和目前的结果表明，抑制Cdk2活化的第1组酪氨酸抑制剂和以有效表皮生长因子受体激酶抑制剂AG1478代表的第2组酪氨酸抑制剂诱导细胞周期停滞。对于HF-1细胞，凋亡和分化。细胞在细胞周期的G（1）阶段以S和G（2）+ M的形式积累。这些化合物在不诱导凋亡或分化的情况下阻止正常角质形成细胞的生长，导致它们在G（1）中积累。属于第4组的AG17主要通过增加G（1）中的细胞分数，同时降低S和G（2）+ M中的细胞分数来发挥其抗增殖作用。

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