Tyrphostins that suppress the growth of human papilloma virus 16-immortalized human keratinocytes

Human papilloma virus 16(HPV16) is considered to be the causative agent for cervical cancer, which ranks second to breast cancer in women's malignanci es. In an attempt to develop drugs that inhibit the malignant transformatio n of HPV16-immortalized epithelial cells, we examined the effect of tyrphos tins on such cells. We examined the effect of tyrphostins from four differe nt families on the growth of HPV16-immortalized human keratinocytes (HF-l) cells. We found that they alter their cell cycle distribution, their morpho logy, and induce cell death by apoptosis. The effects of tyrphostins on HF- 1 cells are different from their effects on normal keratinocytes. Growth su ppression by AG555 and AG1478 is accompanied by 30% apoptosis in HF-I cells , but this is not observed in normal keratinocytes. Tyrphostin treatment pr oduces distinctive morphological changes in HF-1 cells and in normal kerati nocytes; however, the culture organization of normal keratinocytes is less disrupted. These differential effects of the tyrphostins on HPV16-immortali zed keratinocytes compared with their effects on normal keratinocytes sugge sts that these compounds are suitable candidates for the treatment of papil loma. 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 cycl e arrest; and, in the case of HF-1 cells, apoptosis and differentiation. Ce lls 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.