title: Participation of non-neuronal muscarinic receptors in the effect of carbachol with paclitaxel on human breast adenocarcinoma cells. Roles of nitric oxide synthase and arginase.
abstract: Breast cancer is the most common type of cancer in women and represents a major issue in public health. The most frequent methods to treat these tumors are surgery and/or chemotherapy. The latter can exert not only beneficial effects by reducing tumor growth and metastasis, but also toxic actions on normal tissues. Metronomic therapy involves the use of low doses of cytotoxic drugs alone or in combination to improve efficacy and to reduce adverse effects. We have previously reported that breast tumors highly express functional muscarinic acetylcholine receptors (mAChRs) that regulate tumor progression. For this reason, mAChRs could be considered as therapeutic targets in breast cancer. In this paper, we investigated the ability of a combination of the cytotoxic drug paclitaxel plus carbachol, a cholinergic agonist, at low doses, to induce death in breast tumor MCF-7 cells, via mAChR activation, and the role of nitric oxide synthase (NOS) and arginase in this effect. We observed that the combination of carbachol plus paclitaxel at subthreshold doses significantly increased cytotoxicity in tumor cells without affecting MCF-10A cells, derived from human normal mammary gland. This effect was reduced in the presence of the muscarinic antagonist atropine. The combination also increased nitric oxide production by NOS1 and NOS3 via mAChR activation, concomitantly with an up-regulation of NOS3 expression. The latter effects were accompanied by a reduction in arginase II activity. In conclusion, our work demonstrates that mAChRs expressed in breast tumor cells could be considered as candidates to become targets for metronomic therapy in cancer treatment.
authors: Centro de Estudios Farmacológicos y Botánicos (CEFYBO)-(CONICET) 2° Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors: Alejandro Javier
authors: AJ
authors: Español
authors: Centro de Estudios Farmacológicos y Botánicos (CEFYBO)-(CONICET) 2° Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors: Agustina
authors: A
authors: Salem
authors: Centro de Estudios Farmacológicos y Botánicos (CEFYBO)-(CONICET) 2° Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors: Daniela
authors: D
authors: Rojo
authors: Centro de Estudios Farmacológicos y Botánicos (CEFYBO)-(CONICET) 2° Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Argentina. Electronic address: malegazpio@yahoo.com.ar.
authors: María Elena
authors: ME
authors: Sales
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D001119:Arginase / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy*; D002217:Carbachol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*
chemical_list: D011976:Receptors, Muscarinic; D002217:Carbachol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D001119:Arginase; D017239:Paclitaxel
keywords: Arginase; Breast cancer; Muscarinic acetylcholine receptors; Nitric oxide synthase; Paclitaxel