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

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.

<p>Treating advanced breast cancer with metronomic chemotherapy: what is known, what is new and what is the future?</p>

“…The preliminary results of the VICTOR and VEX studies suggest that no additional toxicity occurs with the second and third agents when administered within a mCHT regimen 23,27. Ongoing studies seem to suggest a potential direct antitumoral effect of mCHT 25…”

“…In humans, the OBD ranges between 40 and 50 mg/day 24. Data from a study investigating the effects of metronomic versus standard doses of vinorelbine in in vitro models of triple-negative breast cancer were presented at the AACR-SIC 2017 meeting 25. Overall, relevant anti-proliferative activity was observed in cells treated with metronomic vinorelbine compared with standard protocols.…”

Metronomic Chemotherapy

“…mCHT induces both indirect anti-cancer effects by inhibiting angiogenesis and activating the immune system, and direct anti-cancer actions. Recent studies showed that the combination of vinorelbine plus 5-FU is able to inhibit TNBC cell growth under mCHT schedule while promoting apoptosis and autophagy [ 36 , 37 ]. Other authors have shown that metronomic chemo-endocrine therapy leads to a higher expression of autophagy-related proteins, beclin 1 and LC3, and apoptosis-related markers expression, TUNEL and M30, in HR-positive breast cancer [ 38 ] in comparison to standard therapy.…”

The Premature Senescence in Breast Cancer Treatment Strategy

“…5-fluorouracil should not be considered as a senescence inductor in breast cancer cells. However, it can be an element of senescence-induced combination treatment, as was shown by Cerrito in the case of 5-fluorouracil combination with vinorelbine [ 42 ].…”

“…Cerrito et al showed that vinorelbine and 5-fluorouracil combined (metronomic schedule) treatment can induce senescence, autophagic cell death, and apoptosis, and all those processes can be regarded as an anticancer mechanism in MDA-MB-231 cells. Moreover, they suggested that the induction of senescence and autophagic cell death were especially responsible for the better response of TNBC patients to metronomic therapy than to a standard therapy schedule [ 42 ].…”