1. Farnesyl-transferase inhibitor R115,777 enhances tamoxifen inhibition of MCF-7 cell growth through estrogen receptor dependent and independent pathways
- Author
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Florence Dalenc, Gilles Favre, Jean-Charles Faye, Claire Giamarchi, Marc Poirot, Mélissa Petit, Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Claudius Regaud, This work was supported by INSERM, the French 'Ministère de l'Enseignement Supérieur et de la Recherche', Johnson and Johnson Pharmaceutical Research and Development, together with grants from the 'Groupe de Recherche de l'Institut Claudius Regaud' and the 'Ligue Nationale de Lutte contre le Cancer'., and Autard, Delphine
- Subjects
Pyrrolidines ,MESH: Drug Interactions ,Estrogen receptor ,Apoptosis ,Pharmacology ,Quinolones ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,MESH: Dose-Response Relationship, Drug ,0302 clinical medicine ,Drug Interactions ,Receptor ,0303 health sciences ,Farnesyl Transferase Inhibitor ,MESH: Drug Screening Assays, Antitumor ,MESH: Antineoplastic Agents, Hormonal ,3. Good health ,Receptors, Estrogen ,030220 oncology & carcinogenesis ,MESH: Receptors, Estrogen ,Protein farnesylation ,Female ,Mevalonate pathway ,medicine.drug ,Research Article ,MESH: Cell Line, Tumor ,Antineoplastic Agents, Hormonal ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Breast Neoplasms ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,medicine ,Humans ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Estrogen receptor beta ,030304 developmental biology ,MESH: Quinolones ,MESH: Humans ,MESH: Pyrrolidines ,Dose-Response Relationship, Drug ,Cell growth ,MESH: Apoptosis ,Tamoxifen ,MESH: Research Support, Non-U.S ,[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,Drug Screening Assays, Antitumor ,MESH: Female ,MESH: Breast Neoplasms - Abstract
INTRODUCTION: We have previously shown that FTI-277, a farnesyl transferase inhibitor (FTI), enhances the efficacy of tamoxifen (Tam) in inhibiting the proliferation of the estrogen dependent MCF-7 cell line. As the cellular response to Tam is the result of an inhibition of both estrogen receptor-dependent and -independent pathways, we have used the estrogen receptor selective anti-estrogen ICI182,780 and N-pyrrolidine(-phenylmethyl-phenoxy)-ethanamine-HCl (PBPE), a selective ligand of anti-estrogen binding site (AEBS), to dissect out the mechanism(s) associated with the observed additivity resulting from combination treatment with FTI-277 and Tam. Moreover, for these studies, FTI-277 has been replaced by R115,777, a FTI currently in phase III clinical trials. METHODS: The quantitative sulphorhodamine B (SRB) colorimetric assay was used to determine the growth inhibitory effect of agents on MCF-7 cells. Dose response interactions between R115,777-Tam, R115,777-ICI182,780 and R115,777-PBPE were evaluated, at the IC50 point, using the isobologram method. Apoptotic cell death (DNA fragmentation, nucleus condensation and cytokeratin 18 cleavage) and inhibition of the mevalonate pathway (western blot) were also determined. RESULTS: Combinations of the specific FTI R115,777 with either ICI182,780 or PBPE exhibit a synergistic effect on MCF-7 cell growth inhibition, while its combination with Tam is additive, as previously reported for FTI-277. Apoptosis is detected after treatment with combinations of R115,777 with either Tam or PBPE but not with ICI182,780, suggesting that each combination inhibits cell proliferation by different mechanisms. Even though the ER pathway has not yet been deciphered, it is shown here that the AEBS pathway is able to interfere with the mevalonate pathway at the level of protein farnesylation. CONCLUSION: Overall, this work reveals that combinations of R115,777 with either selective ER ligands or a selective AEBS ligand are able to induce large increases in their anti-proliferative activities on MCF-7 cells. Moreover, these results suggest that it may be of definite interest to evaluate combinations of R115,777 with different anti-estrogens in the treatment of ER positive breast tumours. Based on these experimental data, such combinations may prove beneficial in different clinical scenarios or when used in specific sequences; studying the combination of R115,777 with ICI182,780 for early treatment and reserving combinations with either Tam or a selective AEBS ligand, such as BMS-217380-01, for more resistant disease.
- Published
- 2005