CEFYBO   02669
CENTRO DE ESTUDIOS FARMACOLOGICOS Y BOTANICOS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Benefits of metronomic therapy targeting muscarinic receptors in breast cancer as a sensitizer of cells to classic chemotherapy with paclitaxel
Autor/es:
SANCHEZ, F; SALEM , AGUSTINA; ALEJANDRO ESPAÑOL; SANCHEZ, Y; MARÍA E. SALES; MARTINEZ PULIDO, PAOLA
Reunión:
Congreso; 3rd Global Insight Conference on Breast Cancer; 2018
Resumen:
Resistanceto chemotherapy is a critical problem in cancer treatment and is believed to bedue to the presence of a sub-population of cells named cancer stem cells (CSC).It has been postulated that metronomic therapy (administration of low doses ofdrugs with short inter-dose intervals) could be a useful strategy to over-comethe resistance to traditional chemotherapy. Here, we analyzed the effect of a combination of subthresholdconcentrations of carbachol (CARB) (10-9M) with paclitaxel (PX) (10-11M) onMCF-7 breast cells, derived from a human luminal tumor. The addition of thiscombination during  40 h increased celldeath by 47±6 % (p<0.001 vs. control) measured by an MTT assay, in a similarmanner to 10-6M PX, that also induced death in non-tumorigenic MCF-10A breastcells, an undesirable effect in cancer treatment. In addition, the combinationreduced necrosis (p<0.05 vs. control) and increased apoptosis (p<0.05 vs.control) measured by flow cytometry using annexine-V and 7-AAD. These effectscould be mediated by a reduction of 92±3% (p<0.001 vs. control) in theexpression of ABCG2 protein, that mediates the resistance to chemotherapy,measured by Western blot. We also detected a reduction in CSC population (CD44+/CD24-)by flow cytometry after this first cycle of treatment (p<0.01). Moreover, wedetermined that one cycle treatment with CARB+PX is useful as neo-adjuvanttherapy before PX 10-6M. We can conclude that the metronomic administration ofthis new combination of anti-tumor drugs could be useful not only to promotecancer cell death but also to sensitize tumors cells to traditionalchemotherapy. Resistanceto chemotherapy is a critical problem in cancer treatment and is believed to bedue to the presence of a sub-population of cells named cancer stem cells. Ithas been postulated that metronomic therapy that consists in the administrationof low doses of drugs with short inter-dose intervals could be a usefulstrategy to overcome the resistance to traditional chemotherapy.  Here we analyzed the effect of a combinationof subthreshold concentrations of carbachol with paclitaxel on MCF-7 breast cells derived from a human luminal tumor.Theaddition of this combination during  40 hincreased cell death by 47&plusmn;6 percent (p&lt;0.001 vs. control)measured by an MTT assay in a similar manner than a pharmacologicalconcentration of paclitaxel that also induced death in non-tumorigenic MCF-10Abreast cells an undesirable effect in cancer treatment. In addition thecombination reduced necrosis (p&lt;0.05 vs. control) and increasedapoptosis (p&lt;0.05 vs. control) measured by flow cytometry usingannexine-V and 7-AAD. These effects could be mediated by a reduction of92&plusmn;3 percent (p&lt;0.001 vs. control) in the expression of ABCG2protein that mediates the resistance to chemotherapy. We also detected areduction in cancer stem cell population (CD44+/CD24-) by flow cytometry afterthis first cycle of treatment (p&lt;0.01). Moreover we determined that onecycle treatment with carbachol plus paclitaxel is useful as neo-adjuvanttherapy before a pharmacological concentration of paclitaxel. We can concludethat the metronomic administration of this new combination of anti-tumor drugscould be useful not only to promote cancer cell death but also to sensitizetumor cells to traditional chemotherapy.