Published online Jun 24, 2022. doi: 10.5306/wjco.v13.i6.505
Peer-review started: December 27, 2021
First decision: February 15, 2022
Revised: February 24, 2022
Accepted: April 26, 2022
Article in press: April 26, 2022
Published online: June 24, 2022
Triple negative breast cancer is more aggressive than other breast cancer subtypes and constitutes a public health problem worldwide since it has high morbidity and mortality due to the lack of defined therapeutic targets. Resistance to chemotherapy complicates the course of patients’ treatment. Several authors have highlighted the participation of nicotinic acetylcholine receptors (nAChR) in the modulation of conventional chemotherapy treatment in cancers of the airways. However, in breast cancer, less is known about the effect of nAChR activation by nicotine on chemotherapy treatment in smoking patients.
To investigate the effect of nicotine on paclitaxel treatment and the signaling pathways involved in human breast MDA-MB-231 tumor cells.
Cells were treated with paclitaxel alone or in combination with nicotine, administered for one or three 48-h cycles. The effect of the addition of nicotine (at a concentration similar to that found in passive smokers’ blood) on the treatment with paclitaxel (at a therapeutic concentration) was determined using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The signaling mediators involved in this effect were determined using selective inhibitors. We also investigated nAChR expression, and ATP “binding cassette” G2 drug trans
Our results confirmed that treatment with paclitaxel reduced MDA-MB-231 cell viability in a concentration-dependent manner and that the presence of nicotine reversed the cytotoxic effect induced by paclitaxel by involving the expression of functional α7 and α9 nAChRs in these cells. The action of nicotine on paclitaxel treatment was linked to modulation of the protein kinase C, mitogen-activated protein kinase, extracellular signal-regulated kinase, and NF-κB signaling pathways, and to an up-regulation of ABCG2 protein expression. We also detected that nicotine significantly reduced the increase in cell apoptosis induced by paclitaxel treatment. Moreover, the presence of nicotine reduced the efficacy of paclitaxel treatment administered in three cycles to MDA-MB-231 tumor cells.
Our findings point to nAChRs as responsible for the decrease in the chemotherapeutic effect of paclitaxel in triple negative tumors. Thus, nAChRs should be considered as targets in smoking patients.
Core Tip: Smokers with lung tumors are more likely to generate resistance to chemotherapy than non-smokers. However, little is known about the effect of nicotinic activation during the treatment of breast cancer, a cancer which arises close to the lung. In triple negative human breast cells, nicotine reduces the chemotherapeutic effect of paclitaxel through the participation of several kinases, as well as by modulating ATP “binding cassette” G2 drug transporter expression and inducing resistance to treatment. These results indicate that nicotinic acetylcholine receptors are a new possible target in antitumor therapy for this subtype of breast cancer.