Preclinical Studies Of Ras Inhibitors In Combination With Cytotoxic Therapy

The Ras/Raf pathway has also been shown to play an important role in resistance to cytotoxic therapy. Increased Ras/Raf-1/MEK/MARK activity has been implicated in doxorubicin resistant MCF-7 cell line (57), paclitaxel-resistant cells (58), and the expression of the multidrug resistance (MDR) gene and multidrug resistance protein (MRP) (58-61). Combination of FTIs with doxorubicin (57) or paclitaxel (62-64) leads to additive or synergistic cytotoxicity in vitro. FTIs synergis-tically augment the antimitotic and pro-apoptotic effects of paclitaxel and other microtubule-stabilizing drugs, and result in increased tubulin acetylation (a marker of microtubule stability) (64,65); this effect appears to be a mediated FTI-induced inhibition of histone deacetylase 6 (HDAC6), the only known tubulin dea-cetylase (64).

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