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Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells.
Oncotarget. 2016 Jan 19; 7(3):3548-58.O

Abstract

Auranofin, a gold complex that has been used to treat rheumatoid arthritis in clinics and has documented pharmacokinetic and safety profiles in humans, has recently been investigated for its anticancer activity in leukemia and some solid cancers. However, auranofin's single agent activity in lung cancer is not well characterized. To determine whether auranofin has single agent activity in lung cancer, we evaluated auranofin's activity in a panel of 10 non-small cell lung cancer (NSCLC) cell lines. Cell viability analysis revealed that auranofin induced growth inhibition in a subset of NSCLC cell lines with a half maximal inhibitory concentration (IC50) below 1.0 μM. Treatment with auranofin elicited apoptosis and necroptosis in auranofin-sensitive cell lines. Moreover, the susceptibility of NSCLC cells to auranofin was inversely correlated with TXNRD1 expression in the cells. Transient transfection of the TXNRD1-expressing plasmid in auranofin-sensitive Calu3 cells resulted in partial resistance, indicating that high TXNRD level is one of causal factors for resistance to auranofin. Further mechanistic characterization with proteomic analysis revealed that auranofin inhibits expression and/or phosphorylation of multiple key nodes in the PI3K/AKT/mTOR pathway, including S6, 4EBP1, Rictor, p70S6K, mTOR, TSC2, AKT and GSK3. Ectopic expression of TXNRD1 partially reversed auranofin-mediated PI3K/AKT/mTOR inhibition, suggesting that TXNRD1 may participate in the regulation of PI3K/AKT/mTOR pathway. Administration of auranofin to mice with xenograft tumors derived from NSCLC cells significantly suppressed tumor growth without inducing obvious toxic effects. Our results demonstrated feasibility of repurposing auranofin for treatment of lung cancer.

Authors+Show Affiliations

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Jilin Province Cancer Hospital, Changchun, Jilin, China.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Lymphoma, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.Hamon Center for Therapeutic Oncology, The Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26657290

Citation

Li, Hongyu, et al. "Auranofin-mediated Inhibition of PI3K/AKT/mTOR Axis and Anticancer Activity in Non-small Cell Lung Cancer Cells." Oncotarget, vol. 7, no. 3, 2016, pp. 3548-58.
Li H, Hu J, Wu S, et al. Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells. Oncotarget. 2016;7(3):3548-58.
Li, H., Hu, J., Wu, S., Wang, L., Cao, X., Zhang, X., Dai, B., Cao, M., Shao, R., Zhang, R., Majidi, M., Ji, L., Heymach, J. V., Wang, M., Pan, S., Minna, J., Mehran, R. J., Swisher, S. G., Roth, J. A., & Fang, B. (2016). Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells. Oncotarget, 7(3), 3548-58. https://doi.org/10.18632/oncotarget.6516
Li H, et al. Auranofin-mediated Inhibition of PI3K/AKT/mTOR Axis and Anticancer Activity in Non-small Cell Lung Cancer Cells. Oncotarget. 2016 Jan 19;7(3):3548-58. PubMed PMID: 26657290.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells. AU - Li,Hongyu, AU - Hu,Jing, AU - Wu,Shuhong, AU - Wang,Li, AU - Cao,Xiaobo, AU - Zhang,Xiaoshan, AU - Dai,Bingbing, AU - Cao,Mengru, AU - Shao,Ruping, AU - Zhang,Ran, AU - Majidi,Mourad, AU - Ji,Lin, AU - Heymach,John V, AU - Wang,Michael, AU - Pan,Shiyang, AU - Minna,John, AU - Mehran,Reza J, AU - Swisher,Stephen G, AU - Roth,Jack A, AU - Fang,Bingliang, PY - 2015/08/19/received PY - 2015/11/21/accepted PY - 2015/12/15/entrez PY - 2015/12/15/pubmed PY - 2016/12/15/medline KW - anticancer agent KW - biomarkers KW - drug repurposing KW - lung cancer SP - 3548 EP - 58 JF - Oncotarget JO - Oncotarget VL - 7 IS - 3 N2 - Auranofin, a gold complex that has been used to treat rheumatoid arthritis in clinics and has documented pharmacokinetic and safety profiles in humans, has recently been investigated for its anticancer activity in leukemia and some solid cancers. However, auranofin's single agent activity in lung cancer is not well characterized. To determine whether auranofin has single agent activity in lung cancer, we evaluated auranofin's activity in a panel of 10 non-small cell lung cancer (NSCLC) cell lines. Cell viability analysis revealed that auranofin induced growth inhibition in a subset of NSCLC cell lines with a half maximal inhibitory concentration (IC50) below 1.0 μM. Treatment with auranofin elicited apoptosis and necroptosis in auranofin-sensitive cell lines. Moreover, the susceptibility of NSCLC cells to auranofin was inversely correlated with TXNRD1 expression in the cells. Transient transfection of the TXNRD1-expressing plasmid in auranofin-sensitive Calu3 cells resulted in partial resistance, indicating that high TXNRD level is one of causal factors for resistance to auranofin. Further mechanistic characterization with proteomic analysis revealed that auranofin inhibits expression and/or phosphorylation of multiple key nodes in the PI3K/AKT/mTOR pathway, including S6, 4EBP1, Rictor, p70S6K, mTOR, TSC2, AKT and GSK3. Ectopic expression of TXNRD1 partially reversed auranofin-mediated PI3K/AKT/mTOR inhibition, suggesting that TXNRD1 may participate in the regulation of PI3K/AKT/mTOR pathway. Administration of auranofin to mice with xenograft tumors derived from NSCLC cells significantly suppressed tumor growth without inducing obvious toxic effects. Our results demonstrated feasibility of repurposing auranofin for treatment of lung cancer. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/26657290/Auranofin_mediated_inhibition_of_PI3K/AKT/mTOR_axis_and_anticancer_activity_in_non_small_cell_lung_cancer_cells_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=6516 DB - PRIME DP - Unbound Medicine ER -