Docetaxel induces p53-dependent apoptosis and synergizes with farnesyl transferase inhibitor r115777 in human epithelial cancer cells.
Docetaxel (Taxotere, DTX) is a promoter of apoptosis in cancer cells. Since cytotoxic mechanisms of DTX are not yet fully understood, we have investigated the effects of DTX on apoptosis and ras-->Erk-mediated signal transduction in human epidermoid KB, colon HT-29 and breast HCC1937 cancer cells. We have found that the exposure to 0.78 or 1.56 or 2.5 ng/ml DTX for 48 h induced apoptosis and growth inhibition in about 50 % of KB, HCC1937 and HT-29 cell population, respectively. In these experimental conditions, PARP and caspase 3 cleavage was also showed in all cell lines. KB and HCC1937 cells express a wild type p53 while HT-29 display a mutated form. Interestingly, we have found that DTX reduces the expression of mutated p53 in HT-29 and increases the expression of wild type in KB and HCC1937 cells. Moreover, DTX reduces ubiquitination of the wild type p53 in KB and HCC1937 cells and increases the ubiquitin-conjugated form of mutated p53 in HT-29 cells. Furthermore, exposure of cancer cells to DTX for 48 h increases the expression and activity of Ras and up-regulates Raf-1 and the phosphorylated isoforms of Erk-1/2. On the bases of these data, we have hypothesized that the increased activity of the ras-->erk-dependent pathway induced by DTX could be a protective signalling from the apoptosis caused by the drug. Therefore, we have used R115777, a farnesyl transferase inhibitor that inactivates ras, in combination with DTX. The combined treatment with DTX and R115777 resulted in a strong synergism in growth inhibition in the three cell lines. These data suggest the use of the combination in these therapeutic settings even if further experiments are required for the clinical translation.
Caraglia
M
M
Department of Experimental Oncology, National Institute of Tumours Fondazione G. Pascale, Naples, Italy. Michele.Caraglia@fondazionepascale.it
Giuberti
G
G
Marra
M
M
Di Gennaro
E
E
Facchini
G
G
Caponigro
F
F
Iaffaioli
Rv
R
Budillon
A
A
Abbruzzese
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D000077143:Docetaxel; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D043823:Taxoids; D000077143:Docetaxel; D051231:Farnesyltranstransferase; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins; C402769:tipifarnib