The farnesyl transferase inhibitor R115777 (Zarnestra) synergistically enhances growth inhibition and apoptosis induced on epidermoid cancer cells by Zoledronic acid (Zometa) and Pamidronate
Authors: Annamaria Colao
Giovanni Vitale
Salvatore Venuta
Pierosandro Tagliaferri
Gaia Giuberti
Anna Maria D&#x27;Alessandro
Michele Caraglia
Caterina Viscomi
Alfredo Budillon
Salvatore Del Prete
Pierfrancesco Tassone
Monica Marra
Alberto Abbruzzese
Journal: Oncogene (2004)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Pamidronate; zoledronic acid; aminobisphosphonates; antitumor activity; epidermoid cancer cells
Affiliations: Department of Biochemistry and Biophysics, II University of Naples, Via Costantinopoli no 16, 80138 Naples, Italy. 

Abstract:  Pamidronate (PAM) and zoledronic acid (ZOL) are aminobisphosphonates (BPs) able to affect the isoprenylation of intracellular small G proteins. We have investigated the antitumor activity of BPs and R115777 farnesyl transferase inhibitor (FTI) against epidermoid cancer cells. In human epidermoid head and neck KB and lung H1355 cancer cells, 48 h exposure to PAM and ZOL induced growth inhibition (IC(50) 25 and 10 microM, respectively) and apoptosis and abolished the proliferative and antiapoptotic stimuli induced by epidermal growth factor (EGF). In these experimental conditions, ZOL induced apoptosis through the activation of caspase 3 and a clear fragmentation of PARP was also demonstrated. A strong decrease of basal ras activity and an antagonism on its stimulation by EGF was recorded in the tumor cells exposed to BPs. These effects were paralleled by impaired activation of the survival enzymes extracellular signal regulated kinase 1 and 2 (Erk-1/2) and Akt that were not restored by EGF. Conversely, farnesol induced a recovery of ras activity and antagonized the proapoptotic effects induced by BPs. The combined treatment with BPs and R115777 resulted in a strong synergism both in growth inhibition and apoptosis in KB and H1355 cells. The synergistic activity between the drugs allowed BPs to produce tumor cell growth inhibition and apoptosis at in vivo achievable concentrations (0.1 micromolar for both drugs). Moreover, the combination was highly effective in the inhibition of ras, Erk and Akt activity, while farnesol again antagonized these effects. In conclusion, the combination of BPs and FTI leads to enhanced antitumor activity at clinically achievable drug concentrations that resides in the inhibition of farnesylation-dependent survival pathways and warrants further studies for clinical translation. 

Retracted: No

PubPeer comments:
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 How to explain the duplications? , 
 I find no differences in Figure 2 while the quality of the image does not allow me to express judgments on the similarities of the figure 4 Satsuma Iheyaensis : how do you talk about duplication, at most it can be said of similarities ....... the difference is noticeable ........... is like saying  guilty or  suspected ..... ..... until contrary evidence in civilized countries is only suspected , 
 #5 The onus is on the authors to present images of high enough quality.   is like saying  guilty or  suspected ..... ..... until contrary evidence in civilized countries is only suspected What has that got to do with images which are much more similar than you would expect? , 
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 #2 Figure 2a continued. Much more similar than expected. https: imgur.com AnvUQtL ,