Abstract
BackgroundLung tumors are the leading cause of cancer deaths worldwide and paclitaxel has proven to be useful for patients with lung cancer, however, acquired resistance is a major problem. To overcome this problem, one promising option is the use of Constitutive Androstane Receptor (CAR) ligands in combination with chemotherapeutics against cancer cells. Therefore, we wish to elucidate the effects of CAR ligands on the antineoplastic efficacy of paclitaxel in lung cancer cells.Methodology/Principal FindingsOur results from cell viability assays exposing CAR agonist or inverse-agonist to mouse and human lung cancer cells modulated the antineoplastic effect of paclitaxel. The CAR agonists increased the effect of Paclitaxel in 6 of 7 lung cancer cell lines, whereas the inverse-agonist had no effect on paclitaxel cytotoxicity. Interestingly, the mCAR agonist TCPOBOP enhanced the expression of two tumor suppressor genes, namely WT1 and MGMT, which were additively enhanced in cells treated with CAR agonist in combination with paclitaxel. Also, in silico analysis showed that both paclitaxel and CAR agonist TCPOBOP docked into the mCAR structure but not the inverse agonist androstenol. Paclitaxel per se increases the expression of CAR in cancer cells. At last, we analyzed the expression of CAR in two public independent studies from The Cancer Genome Atlas (TCGA) of Non Small Cell Lung Cancer (NSCLC). CAR is expressed in variable levels in NSCLC samples and no association with overall survival was noted.Conclusions/SignificanceTaken together, our results demonstrated that CAR agonists modulate the antineoplastic efficacy of paclitaxel in mouse and human cancer cell lines. This effect was probably related by the enhanced expression of two tumor suppressor genes, viz. WT1 and MGMT. Most of NSCLC cases present CAR gene expression turning it possible to speculate the use of CAR modulation by ligands along with Paclitaxel in NSCLC therapy.
Highlights
Lung tumors are the leading cause of cancer deaths worldwide, and they are responsible for estimated 1.2 million deaths per year [1]
We evaluated the cytotoxic effects of mCAR ligands, including the agonist TCPOBOP and the inverse agonist androstenol, on E9 mouse lung cancer cells
The inverse-agonist androstenol induced a dose-dependent increase in cell proliferation, with more than 60% cells than the control group in the high concentration (p,0.0001; Fig. 1). These results suggest that the use of mCAR agonists in mouse cancer cells might result in different effects on cell viability, even increasing cell proliferation as observed for androstenol
Summary
Lung tumors are the leading cause of cancer deaths worldwide, and they are responsible for estimated 1.2 million deaths per year [1]. The most common treatment approaches include a combination of surgery (when tumors are resectable), radiotherapy and chemotherapy Regarding the latter, the use of one or more cytotoxic drugs at the same time, such as taxanes, platinum compounds, and/or nucleoside analogs is most common. Lung tumors are the leading cause of cancer deaths worldwide and paclitaxel has proven to be useful for patients with lung cancer, acquired resistance is a major problem. To overcome this problem, one promising option is the use of Constitutive Androstane Receptor (CAR) ligands in combination with chemotherapeutics against cancer cells. We wish to elucidate the effects of CAR ligands on the antineoplastic efficacy of paclitaxel in lung cancer cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
