Metronomic therapy focused on cholinergic receptors to treat cancer. Are nicotinic receptors involved?

SALES ME

Long Beach

Simposio; 5th International Symposium on Non-Neuronal Acetylcholine; 2019

University of California Irvine

Breast cancer is yet the most frequent type of malignancy in women and represents a major problem for public health. Breast cancer is a heterogeneous disease in which 4 main tumor subtypes have been described: 1) Luminal A, positive estrogen receptor (ER +); 2) Luminal B, RE +, progesterone receptor (RP) +; 3) HER2 + (amplification of the HER2 / neu oncogene); 4) Triple Negative (TN) (RE- / RP- / HER2-). Luminal and triple negative (TN) represent the two opposite ends of the molecular classification of breast tumors and they thoroughly differ regarding treatment and patients´ survival. Since TN tumors lack of a specific therapeutic target, conventional chemotherapy besides surgery and radiotherapy, has been used with low successful. For this reason metronomic therapy, based in the administration of low doses of conventional or non-conventional drugs, with short intervals inter-doses has been attempted. We have previously reported that muscarinic acetylcholine receptors (mAChRs) are expressed either in luminal or in TN tumors but they are absent in normal breast cells pointing them as selective targets for breast cancer treatment. The administration of muscarinic agonists triggered cell death, moreover the combination of low doses of paclitaxel (PX) or doxorubicin with muscarinic agonists, reduces cell viability in vitro, migration, angiogenic response and tumor growth in TN tumors. On the contrary, nicotinic receptors (nAChRs) are expressed in TN tumors but also in non-tumorigenic breast cells and their activation with nicotine increased proliferation in a dose-dependent manner. The combination of PX with nicotine at low concentrations significantly reduced the cytotoxic action of PX. These results could be indicating the ability of nicotine to reduce the effectiveness of breast cancer chemotherapy.