Inhibitors of Ras farnesylation revert the increased resistance to oxidative stress in K-Ras transformed NIH 3T3 cells.
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.
Santillo
M
M
Dipartimento di Neuroscienze, Sezione Fisiologia, Università degli Studi di Napoli "Federico II", Napoli, Italy. marsanti@cds.unina.it
Mondola
P
P
Gioielli
A
A
Serù
R
R
Iossa
S
S
Annella
T
T
Vitale
M
M
Bifulco
M
M
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D011905:Genes, ras; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D063065:Organophosphonates / Q000494:pharmacology*; D018384:Oxidative Stress; D017368:Protein Prenylation / Q000187:drug effects*
D000970:Antineoplastic Agents; D063065:Organophosphonates; D008148:Lovastatin