Metronomic combination of Vinorelbine and 5Fluorouracil is able to inhibit triple-negative breast cancer cells. Results from the proof-of-concept VICTOR-0 study

Abstract

// Maria Grazia Cerrito 1 , Marco De Giorgi 1 , Davide Pelizzoni 1, 2 , Sara Maria Bonomo 1 , Nunzio Digiacomo 1, 2 , Arianna Scagliotti 1 , Cristina Bugarin 4 , Giuseppe Gaipa 4 , Emanuela Grassilli 1 , Marialuisa Lavitrano 1 , Roberto Giovannoni 1 , Paolo Bidoli 1, 2 and Marina Elena Cazzaniga 1, 2, 3 1 Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy 2 Oncology Unit, ASST Monza, Monza 20900, Italy 3 Phase 1 Research Centre, Monza 20900, Italy 4 M.Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, Monza 20900, Italy Correspondence to: Maria Grazia Cerrito, email: mariagrazia.cerrito@unimib.it Keywords: triple-negative breast cancer; 5-fluorouracil; vinorelbine; metronomic combination; LC3A/B Received: November 11, 2017      Accepted: May 01, 2018      Published: June 08, 2018 ABSTRACT Triple Negative Breast Cancer (TNBC) is an aggressive neoplasia with median Overall Survival (OS) less than two years. Despite the availability of new drugs, the chance of survival of these patients did not increase. The combination of low doses of drugs in a metronomic schedule showed efficacy in clinical trials, exhibiting an anti-proliferative and anti-tumour activity. In Victor-2 study we recently evaluated a new metronomic combination (mCHT) of Capecitabine (CAPE) and Vinorelbine (VNR) in breast cancer patients showing a disease control rate with a median Progression-Free Survival (PFS) of 4.7 months in 28 TNBC patients. Here in Victor-0 study, we examined the effect of mCHT vs standard (STD) schedule of administration of different combinations of 5-Fluorouracil (5FU), the active metabolite of CAPE, and VNR in TNBC cell lines MDA-MB-231 and BT-549. A significant anti-proliferative activity was observed in cells treated with metronomic vs STD administration of 5FU or VNR alone. Combination of the two drugs showed an additive inhibitor effect on cell growth in both cell lines. Moreover, after exposure of cells to 5FU and VNR under mCHT or conventional schedule of administration we also observed a downregulation of chemoresistance factor Bcl-2, changes in pro-apoptotic protein Bax and in cleaved effector caspase-3 and increased expression of LC3A/B autophagy protein. Our results therefore suggest that molecular mechanisms implicated in apoptosis and autophagy as well as the cross-talk between these two forms of cell death in MDA-MB-231 and BT-549 cells treated with 5FU and VNR is dose- and schedule-dependent and provide some insights about the roles of autophagy and senescence in 5FU/VNR-induced cell death.