The HER-2/neu gene product, p185(neu), is a membrane-bound receptor with
tyrosine kinase activity. High levels of p185(neu) is correlated with intrinsic chemoresistance of
non-small cell lung cancer (NSCLC) cell lines. We investigated the effects of
tyrphostin AG825, a selective
tyrosine kinase inhibitor preferentially inhibiting HER-2/neu
kinase, on the chemosensitivities and on the
drug-induced cell cycle changes of NSCLC cell lines that expressed different levels of p185(neu). Compared to the low-p185(neu) expressing cell lines, we found that the high-p185(neu) expressing cell lines were more resistant to
doxorubicin,
etoposide, and
cis-diamminedichloroplatinum(II) but more sensitive to
AG825.
AG825 was able to significantly enhance the chemosensitivities of the high-p185(neu) expressing cell lines, whereas it had little effect on the chemosensitivities of the low-p185(neu) expressing cells, with a few exceptions in which minor antagonistic effects were observed. Although high concentrations of
AG825 could reduce the
drug-induced G(2) arrest that was accompanied by the activation of phosphorylated p34(cdc2), we failed to find any remarkably differential effects of
AG825 on
drug-induced G(2), arrest and the accompanying phosphorylation status of p34(cdc2) of the high- and and the low-p185(neu) expressing cell lines. In summary,
tyrphostin AG825 can enhance chemosensitivity in high- but not in low-p185(neu) expressing NSCLC cell lines. This differential effect cannot be explained by the alterations of
drug-induced cell cycle changes by
AG825. Our results provide a rationale to develop p185(neu)- specific
tyrphostin and to test them in combination with
anticancer agents in vivo and in clinical trials.