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Enhancement of chemosensitivity by tyrphostin AG825 in high-p185(neu) expressing non-small cell lung cancer cells.

Abstract
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.
AuthorsC M Tsai, A Levitzki, L H Wu, K T Chang, C C Cheng, A Gazit, R P Perng
JournalCancer research (Cancer Res) Vol. 56 Issue 5 Pg. 1068-74 (Mar 01 1996) ISSN: 0008-5472 [Print] United States
PMID8640763 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzothiazoles
  • Benzylidene Compounds
  • Nitriles
  • Tyrphostins
  • tyrphostin AG825
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2
Topics
  • Benzothiazoles
  • Benzylidene Compounds (pharmacology)
  • Carcinoma, Non-Small-Cell Lung (metabolism, pathology)
  • Cell Division (drug effects)
  • Drug Resistance
  • Humans
  • Lung Neoplasms (metabolism, pathology)
  • Nitriles (pharmacology)
  • Protein-Tyrosine Kinases (antagonists & inhibitors)
  • Receptor, ErbB-2 (biosynthesis)
  • Tumor Cells, Cultured
  • Tyrphostins

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