Mitogen-activated protein kinase antisense oligonucleotide inhibits the growth of human lung cancer cells

Mitogen-activated protein kinase (MAPK) pathway is proposed to be a therape utic target for cancer cells. In order to find the potential therapeutic us efulness of MAPK for cancer cells, the effect of EAS1, an antisense oligonu cleotide for an MAPK, on cancer-cell-growth were investigated in vitro. EAS 1 effectively inhibited the growth of several human lung cancer cell lines such as PC-14 cells upon exposure to 10(-0)-10(-1) mu M of EAS1 determined dye-formation (MTT) assay. The ED50 values were comparable to those obtaine d for the inhibition of MAPK activity, DNA synthesis. EAS1 arrested the PC- 14 cells at the G2/M phase of cell cycle followed by apoptosis in a dose-de pendent manner. In order to determine the factors which influence the cellu lar sensitivity against MAPK inhibition, the effect of EAS1 on H-ms-transfo rmed murine fibroblast cells were compared with that on parental cells. The NIH3T3 cells transformed by the H-ms gene (PT22-3) showed higher sensitivi ty against the effects of EAS1. Because MAPK activity was activated by H-ms gene transfection in PT22-3, the status of the MAPK cascade in cells was t he determining factor for the efficacy of EAS1. In addition, cell permeabil ization by digitonin enhanced the growth inhibitory effect of EAS1. Penetra tion of the cell membrane by EAS1 is also crucial for the growth inhibitory effect of EAS1. In conclusion, MAPK is an important target for cancer trea tment and MAPK antisense oligonucleotide is a potentially significant antit umor oligonucleotide.