In order to obtain additional information on the involvement of
protein kinase C (PKC)
isoenzymes in the resistance of cells to anticancer drugs and in the induction of apoptosis, we employed
antisense oligonucleotides to PKC alpha and PKC zeta,
CGP 53506, a new inhibitor of PKC alpha, and cells overexpressing PKC alpha,
PKC epsilon and PKC zeta. We found that in HeLa cells which express PKC alpha and zeta, 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 overexpressing NIH3T3 cells more than that of wild-type cells and induced apoptosis, indicating that such a PKC alpha inhibitor may be useful in the treatment of
tumors overexpressing PKC alpha such as
glioblastomas. NIH3T3 cells overexpressing PKC alpha were more resistant, whereas NIH3T3 cells overexpressing
PKC epsilon or PKC zeta were more sensitive to treatment with cis-platin,
adriamycin or gamma-irradiation compared to parental NIH3T3 wild-type cells. The observed resistance and sensitization corresponded to the extent of apoptosis induced by these treatments. Alterations in the expression of p53, bcl-2 and bax in the PKC
isoenzyme overexpressing cells indicate that these
proteins may be involved in the different sensitivities of these cells.