13 research outputs found
Farnesyltransferase inhibitors and human malignant pleural mesothelioma: a first-step comparative translational study.
It is known that the potential clinical use of farnesyltransferase
inhibitors (FTI) could be expanded to include
cancers harboring activated receptor tyrosine kinases.
Approximately 70% of malignant pleural mesotheliomas
(MPM) overexpress epidermal growth factor receptors
(EGFR) and a subset express both EGFR and transforming
growth factor A (TGF-A), suggesting an autocrine role for
EGFR in MPM. We checked on MPM cells (10 human cell
lines, 11 primary cultures obtained by human biopsies, and
7 short-term normal mesothelial cell cultures) concerning the
following: (a) the relative overexpression of EGFR (Western
blotting, flow cytometry, immunohistochemistry), (b) the
relative expression of EGFR ligands (EGF, amphiregulin,
TGF-A, ELISA), (c) the relative increase of the activated
form of Ras (Ras-bound GTP) after EGF stimulation (Ras
activation assay), (d) the efficacy of five different FTIs (HDJ2
prenylation, cell cytotoxicity, and apoptosis using ApopTag
and gel ladder). EGFR was overexpressed in MPM cells
compared with normal pleural mesothelial cells in equivalent
levels as in non\u2013small cell lung cancer cells A549.
MPM cells constitutively expressed EGFR ligands; however,
Ras activation was attenuated at high EGF concentrations
(100 ng/mL). Growth of MPM cells was substantially not
affected by treatment with different FTIs (SCH66336, BMS-
214662, R115777, RPR-115135, and Manumycin). Among
these, BMS-214662 was the only one moderately active.
BMS-214662 triggered apoptosis in a small fraction of cells
(not higher than 30%) that was paralleled by a slight
decrease in the levels of TGF-A secreted by treated MPM
cells. Our data highlighted the concept that the same
signaling pathway can be regulated in different ways and
these regulations can differ between different cells of
different origin