Farnesyltransferase inhibitors (FTIs)
are a class of oral anti-cancer drugs currently tested
in phase I-II clinical trials for treatment of
hematological malignancies. The in vitro effects of
various FTIs (alpha-hydroxyfarnesylphosphonic
acid, manumycin-A and SCH66336) were tested on
CD34+ KG1a cell line and in primary acute myeloid
leukemia (AML) cells from 64 patients. By cell
viability and clonogeneic methylcellulose assays,
FTIs showed a significant inhibitory activity in
CD34+ KG1a and primary bone marrow (BM)
leukemic cells from 56% of AML patients. FTIs also
induced activation of caspase-3 and Fas-independent
apoptosis, confirmed by the finding that inhibition of
caspase-8 was not associated with the rescue of FTItreated cells. We concluded that other cellular events
induced by FTIs may trigger activation of caspase-3
and subsequent apoptosis, but the expression of
proapoptotic molecules, as Bcl-2 and Bcl-XL, and
antiapoptotic, as Bcl-X(s), were not modified by
FTIs. By contrast, expression of inducible nitric
oxide synthase (iNOS) was increased in FTI-treated
AML cells. Our results suggest a very complex
mechanism of action of FTIs that require more
studies for a better clinical use of the drugs alone or
in combination in the treatment of hematological
malignancies
