Constitutive androstane receptor ligands modulate the anti-tumor efficacy of paclitaxel in non-small cell lung cancer cells.

Abstract

BACKGROUND:

Lung 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 FINDINGS:

Our 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/SIGNIFICANCE:

Taken 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.

• Authors: Heidge Fukumasu, Arina L Rochetti, Pedro R L Pires, Edson R Silva, Ligia G Mesquita, Ricardo F Strefezzi, Daniel D De Carvalho, Maria L Dagli
• Journal: PloS one (PLoS One) Vol. 9 Issue 6 Pg. e99484 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24959746 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androstenols
• Antineoplastic Agents
• Constitutive Androstane Receptor
• Oximes
• Pyridines
• Receptors, Cytoplasmic and Nuclear
• Thiazoles
• WT1 Proteins
• 1,4-bis(2-(3,5-dichloropyridyloxy))benzene
• 6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime
• DNA Modification Methylases
• Paclitaxel

Topics

• Androstenols (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (metabolism)
• Cell Line, Tumor
• Constitutive Androstane Receptor
• DNA Modification Methylases (metabolism)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (metabolism)
• Mice
• Oximes (pharmacology)
• Paclitaxel (pharmacology)
• Pyridines (pharmacology)
• Receptors, Cytoplasmic and Nuclear (agonists)
• Thiazoles (pharmacology)
• WT1 Proteins (metabolism)