title: In VitroApoptotic Effects of Farnesyltransferase blockade in Acute Myeloid Leukemia Cells.
abstract: Farnesyltransferase inhibitors (FTIs) are a class of oral anti-cancer drugs currently tested in phase I-II clinical trials for treatment of hematological malignancies. Thein vitroeffects 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 FTI-treated 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.
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Giudice
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ricci
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Marino
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Rocco
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Villani
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Langella
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Manente
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Seneca
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Ferrara
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Pezzullo
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Serio
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Selleri
keywords: acute myeloid leukemia; apoptosis; farnesyltransferase inhibitors; nitric oxide