The involvement of protein kinase C isoenzymes alpha, epsilon and zeta in the sensitivity to antitumor treatment and apoptosis induction

In order to obtain additional information on the involvement of protein kin ase C (PKC) isoenzymes in the resistance of cells to anticancer drugs and i n the induction of apoptosis, we employed antisense oligonucleotides to PKC alpha and PKC zeta, CGP 53506, a new inhibitor of PKC alpha, and cells ove rexpressing PKC alpha, PKC epsilon and PKC zeta. We found that in HeLa cell s which express PKC alpha and alpha, down-modulation of either PKC alpha or PKC zeta with antisense oligonucleotides induced apoptosis. The PKC alpha selective inhibitor CGP 53506 reduced the proliferation rate of PKC alpha o verexpressing NIH3T3 cells more than that of wild-type cells and induced ap optosis. indicating that such a PKC alpha inhibitor may be useful in the tr eatment of tumors over expressing PKC alpha such as glioblastomas. NIH3T3 c ells overexpressing PKC alpha were more resistant, whereas NIH3T3 cells ove rexpressing PKC epsilon or PKC zeta. were more sensitive to treatment with cis-platin, adriamycin or gamma-irradiation compared to parental NIH3T3 wil d-type cells. The observed resistance and sensitization corresponded to the extent of apoptosis induced by these treatments. Alterations in the expres sion of p53, bcl-2 and bar in the PKC isoenzyme overexpressing cells indica te that these proteins may be involvd in the different sensitivities of the se cells.