K-Ras-independent effects of the farnesyl transferase inhibitor L-744,832 on cyclin B1/Cdc2 kinase activity, G2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cells

• Published in: Neoplasia (New York, N.Y.) Vol. 2; no. 3; pp. 261 - 272
• Main Authors: Song, S Y, Meszoely, I M, Coffey, R J, Pietenpol, J A, Leach, S D
• Format: Journal Article
• Language: English
• Published: United States 01.05.2000
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Carcinoma, Ductal, Breast - pathology; Cyclin B - metabolism; Cyclin B1; Enzyme Inhibitors - pharmacology; G2 Phase - drug effects; Genes, ras - physiology; Humans; Methionine - analogs & derivatives; Methionine - pharmacology; Mitosis - drug effects; Pancreatic Neoplasms - pathology
• ISSN: 1522-8002
• DOI: 10.1038/sj.neo.7900088

Pancreatic ductal adenocarcinoma is a highly lethal malignancy that is resistant to traditional cytotoxic therapy. High rates of activating codon 12 K-Ras mutations in this disease have generated considerable interest in the therapeutic application of novel farnesyl transferase inhibitors (FTIs). However, a comprehensive analysis of the effects of FTI treatment on pancreatic cancer cells has not been performed. Treatment of five different human pancreatic cancer cell lines with FTI L-744,832 resulted in inhibition of anchorage-dependent growth, with wide variation in sensitivity among different lines. Effective growth inhibition by L-744,832 correlated with accumulation of cells with a tetraploid (4N) DNA content and high levels of cyclin B1/cdc2 kinase activity, implying cell cycle arrest downstream from the DNA damage-inducible G2/M cell cycle checkpoint. In addition, sensitive cell lines underwent apoptosis as evidenced by changes in nuclear morphology and internucleosomal DNA fragmentation. L-744,832 at a concentration of 1 microM additively enhanced the cytotoxic effect of ionizing radiation, apparently by overriding G2/M checkpoint activation. The effects of FTI treatment on cell growth and cell cycle regulation were associated with changes in posttranslational processing of H-Ras and N-Ras, but not K-Ras. The results confirm the potential therapeutic efficacy of FTI treatment in pancreatic cancer, and suggest that farnesylated proteins other than K-Ras may act as important regulators of G2/M cell cycle kinetics.