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The farnesyl transferase inhibitor R115777 (Zarnestra®) synergistically enhances growth inhibition and apoptosis induced on epidermoid cancer cells by Zoledronic acid (Zometa®) and Pamidronate

Oncogene volume 23, pages 6900–6913 (2004)Cite this article

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 (IC50 25 and 10 μ M, 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 μmolar 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.

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Acknowledgements

This work was supported by grants from Italian Minister for Research (PRIN2003) and Italian Minister of Health (FSN 2003).

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, II University of Naples, Via Costantinopoli no 16, Naples, 80138, Italy

    Michele Caraglia, Anna Maria D'Alessandro, Monica Marra, Gaia Giuberti & Alberto Abbruzzese

  2. Department of Molecular and Clinical Endocrinology and Oncology, ‘Federico II’ University of Naples, Italy

    Giovanni Vitale & Annamaria Colao

  3. Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Italy

    Caterina Viscomi, Pierosandro Tagliaferri, Pierfrancesco Tassone & Salvatore Venuta

  4. Oncology Department, Frattamaggiore, ASL NA3, Italy

    Salvatore Del Prete

  5. National Cancer Institute of Naples ‘Fondazione G. Pascale’, Italy

    Alfredo Budillon

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  1. Michele Caraglia
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Correspondence to Michele Caraglia or Alberto Abbruzzese.

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Caraglia, M., D'Alessandro, A., Marra, M. et al. The farnesyl transferase inhibitor R115777 (Zarnestra®) synergistically enhances growth inhibition and apoptosis induced on epidermoid cancer cells by Zoledronic acid (Zometa®) and Pamidronate. Oncogene 23, 6900–6913 (2004). https://doi.org/10.1038/sj.onc.1207814

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