Inhibitors of Ras farnesylation revert the increased resistance to oxidative stress in K-Ras transformed NIH 3T3 cells

• Published in: Biochemical and biophysical research communications Vol. 229; no. 3; pp. 739 - 745
• Main Authors: Santillo, M, Mondola, P, Gioielli, A, Serù, R, Iossa, S, Annella, T, Vitale, M, Bifulco, M
• Format: Journal Article
• Language: English
• Published: United States 24.12.1996
• Subjects: 3T3 Cells; Animals; Antineoplastic Agents - pharmacology; Cell Transformation, Neoplastic - metabolism; Genes, ras; Lovastatin - pharmacology; Mice; Organophosphonates - pharmacology; Oxidative Stress; Protein Prenylation - drug effects
• ISSN: 0006-291X
• DOI: 10.1006/bbrc.1996.1874

Tumor resistance to oxidative stress prevents the efficacy of cancer therapy based upon a free radical-mediated mechanism. K-ras transformed NIH 3T3 cells (E32-4-2) showed, under oxidative stress, reactive oxygen species (ROS) levels 10-fold lower and lipid peroxide levels 56% lower, compared to their nontransformed counterpart. Since p21(ras) activity depends upon farnesylation, we tested the effect of the inhibitors of farnesylation lovastatin and (alpha-hydroxyfarnesyl) phosphonic acid on susceptibility to oxidative stress in these cells. Preincubation of cells for 24 h with 10 microM lovastatin resulted in a 10-fold increase of ROS levels and a 50% increase of lipid peroxide levels measured under pro-oxidant conditions. Similarly, preincubation of cells with 100 microM (alpha-hydroxyfarnesyl) phosphonic acid for 24 h enhanced stress-induced levels of either ROS (7.5-fold) or lipid peroxides (33%). The effect of lovastatin and (alpha-hydroxyfarnesyl) phosphonic acid is specifically due to their ability to inhibit p21(ras) activity. In fact, inhibition of p21(ras) by transfecting E32-4-2 cells with the transdominant negative mutant of H-ras (L61, S186) led, analogously to lovastatin or (alpha-hydroxyfarnesyl) phosphonic acid treatment, to a strong increase of stress-induced ROS levels. These results suggest that farnesylation inhibitors could be used as an adjuvant therapy to improve the tumoricidal effect of cancer treatment based upon free-radical production in ras-dependent tumors.