Benefits of metronomic therapy targeting muscarinic receptors in breast cancer as a sensitizer of cells to classic chemotherapy with paclitaxel

Abstract

Resistance to chemotherapy is a critical problem in cancer treatment and is believed to be due to the presence of a subpopulation of tumor cells named cancer stem cells. It has been postulated that metronomic therapy that consists in the administration of low doses of drugs with short inter-dose intervals could be a useful strategy to overcome the resistance to traditional chemotherapy. Here we analyzed the effect of a combination of subthreshold concentrations of carbachol with paclitaxel on MCF-7 breast cancer cells.The addition of this combination during 40 h increased cell death by 47±6 percent (p<0.001 vs. control) measured by an MTT assay. This effect was similar to that produced by a pharmacological concentration of paclitaxel that also induced death in non-tumorigenic MCF-10A breast cells an undesirable effect in cancer treatment. In addition the combination reduced 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 effects could be mediated by a reduction of 92±3 percent (p<0.001 vs. control) in the expression of ABCG2 protein that mediates the resistance to chemotherapy. We also detected a reduction in cancer stem cell population (CD44+/CD24-) by flow cytometry after this first cycle of treatment (p<0.01). Moreover we determined that one cycle treatment with carbachol plus paclitaxel is useful as neo-adjuvant therapy before the addition of a pharmacological concentration of paclitaxel. We can conclude that the metronomic administration of this new combination of anti-tumor drugs could be useful not only to promote cancer cell death but also to sensitize tumor cells to traditional chemotherapy.