{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:59:17Z","timestamp":1787313557372,"version":"build-2736575974"},"reference-count":75,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81673580"],"award-info":[{"award-number":["81673580"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Youth Innovation Promotion Association of the Chinese Academy of Sciences","award":["2020337"],"award-info":[{"award-number":["2020337"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Warburgia ugandensis Sprague (WU) is a traditional medicinal plant used for the treatment of various diseases, including cancer, in Africa. This study aimed to evaluate the anti-non-small cell lung cancer (NSCLC) activities of WU against A549 cells and to reveal potential molecular mechanisms. The cytotoxicity of various WU extracts was evaluated with HeLa (cervical cancer), HepG2 (liver cancer), HT-29 (colorectal cancer), and A549 (non-small cell lung cancer) cells by means of Sulforhodamine B (SRB) assay. Therein, the dimethyl carbonate extract of WU (WUD) was tested with the most potent anti-proliferative activity against the four cancer cell lines, and its effects on cell viability, cell cycle progression, DNA damage, intracellular reactive oxygen species (ROS), and expression levels of G0\/G1-related proteins in A549 cells were further examined. First, it was found that WUD inhibited the proliferation of A549 cells in a time- and dose-dependent manner. In addition, WUD induced G0\/G1 phase arrest and modulated the expression of G0\/G1 phase-associated proteins Cyclin D1, Cyclin E1, and P27 in A549 cells. Furthermore, WUD increased the protein abundance of P27 by inhibiting FOXO3A\/SKP2 axis-mediated protein degradation and also significantly induced the \u03b3H2AX expression and intracellular ROS generation of A549 cells. It was also found that the inhibitory effect of WUD on the proliferation and G0\/G1 cell cycle progression of A549 cells could be attenuated by NAC, a ROS scavenger. On the other hand, phytochemical analysis of WUD with UPLC-QTOF-MS\/MS indicated 10 sesquiterpenoid compounds. In conclusion, WUD exhibited remarkable anti-proliferative effects on A549 cells by improving the intracellular ROS level and by subsequently modulating the cell proliferation and G0\/G1 cell cycle progression of A549 cells. These findings proved the good therapeutic potential of WU for the treatment of NSCLC.<\/jats:p>","DOI":"10.3390\/antiox10101559","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T10:22:42Z","timestamp":1632997362000},"page":"1559","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Stimulation of ROS Generation by Extract of Warburgia ugandensis Leading to G0\/G1 Cell Cycle Arrest and Antiproliferation in A549 Cells"],"prefix":"10.3390","volume":"10","author":[{"given":"Yong-Li","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan 430074, China"},{"name":"The Sino-Africa Joint Research Center, Chinese Academy of Sciences, Wuhan 430074, China"},{"name":"Innovation Academy for Drug Discovery and Development, Chinese Academy of Sciences, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui-Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan 430074, China"},{"name":"The Sino-Africa Joint Research Center, Chinese Academy of Sciences, Wuhan 430074, China"},{"name":"Innovation Academy for Drug Discovery and Development, Chinese Academy of Sciences, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan 430074, China"},{"name":"The Sino-Africa Joint Research Center, Chinese Academy of Sciences, Wuhan 430074, China"},{"name":"Innovation Academy for Drug Discovery and Development, Chinese Academy of Sciences, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Cui","family":"Zhuang","sequence":"additional","affiliation":[{"name":"School of Chemical Biology and Environment, Yuxi Normal University, Yuxi 653100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Quan","family":"Guo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan 430074, China"},{"name":"The Sino-Africa Joint Research Center, Chinese Academy of Sciences, Wuhan 430074, China"},{"name":"Innovation Academy for Drug Discovery and Development, Chinese Academy of Sciences, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"112742","DOI":"10.1016\/j.jep.2020.112742","article-title":"Ethnobotanical study of selected medicinal plants traditionally used in the rural Greater Mpigi region of Uganda","volume":"256","author":"Schultz","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.jep.2015.02.021","article-title":"Warburgia: A comprehensive review of the botany, traditional uses and phytochemistry","volume":"165","author":"Leonard","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s11655-019-3042-6","article-title":"Ethnopharmacological potentials of Warburgia ugandensis on antimicrobial activities","volume":"27","author":"Okello","year":"2019","journal-title":"Chin. J. Integr. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.jep.2010.04.034","article-title":"Prophylactic and curative activities of extracts from Warburgia ugandensis Sprague (Canellaceae) and Zanthoxylum usambarense (Engl.) Kokwaro (Rutaceae) against Plasmodium knowlesi and Plasmodium berghei","volume":"130","author":"Were","year":"2010","journal-title":"J. Ethnopharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3322\/caac.20107","article-title":"Global cancer statistics","volume":"61","author":"Jemal","year":"2011","journal-title":"CA-Cancer J. Clin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA-Cancer J. Clin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.lungcan.2019.09.017","article-title":"Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC)","volume":"137","author":"Gelatti","year":"2019","journal-title":"Lung Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA-Cancer J. Clin."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.lungcan.2020.06.010","article-title":"Combination of computed tomography-guided iodine-125 brachytherapy and bronchial arterial chemoembolization for locally advanced stage III non-small cell lung cancer after failure of concurrent chemoradiotherapy","volume":"146","author":"Chen","year":"2020","journal-title":"Lung Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1093\/nutrit\/nuz027","article-title":"The conundrum of dietary antioxidants in cancer chemotherapy","volume":"78","author":"Ilghami","year":"2020","journal-title":"Nutr. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural products as sources of new drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1159\/000336462","article-title":"Prognostic and predictive value of cell cycle deregulation in non-small-cell lung cancer","volume":"79","author":"Sterlacci","year":"2012","journal-title":"Pathobiology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12483","DOI":"10.1093\/nar\/gkaa1002","article-title":"A unified model for the G1\/S cell cycle transition","volume":"48","author":"Hume","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.biopha.2018.04.080","article-title":"CDK16 overexpressed in non-small cell lung cancer and regulates cancer cell growth and apoptosis via a p27-dependent mechanism","volume":"103","author":"Wang","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0169-5002(99)00085-9","article-title":"The cyclin-dependent kinase inhibitor p27 as a prognostic factor in advanced non-small cell lung cancer: Its immunohistochemical evaluation using biopsy specimens","volume":"26","author":"Ishihara","year":"1999","journal-title":"Lung Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nrc2347","article-title":"The Cdk inhibitor p27 in human cancer: Prognostic potential and relevance to anticancer therapy","volume":"8","author":"Chu","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.biocel.2015.08.005","article-title":"p27(Kip1) signaling: Transcriptional and post-translational regulation","volume":"68","author":"Hnit","year":"2015","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/nrc2396","article-title":"Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: Tipping the scales of cancer","volume":"8","author":"Frescas","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e693","DOI":"10.1038\/cddis.2013.223","article-title":"Salinomycin induces cell death via inactivation of Stat3 and downregulation of Skp2","volume":"4","author":"Koo","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, F., Dong, X., Lin, P., and Jiang, J. (2018). Regulation of Akt\/FoxO3a\/Skp2 axis is critically involved in berberine-induced cell cycle arrest in hepatocellular carcinoma cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020327"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1007\/s10495-017-1424-9","article-title":"Induction of reactive oxygen species: An emerging approach for cancer therapy","volume":"22","author":"Zou","year":"2017","journal-title":"Apoptosis"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1186\/s13046-018-0909-x","article-title":"The role of cellular reactive oxygen species in cancer chemotherapy","volume":"37","author":"Yang","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Aggarwal, V., Tuli, H.S., Varol, A., Thakral, F., Yerer, M.B., Sak, K., Varol, M., Jain, A., Khan, M.A., and Sethi, G. (2019). Role of reactive oxygen species in cancer progression: Molecular mechanisms and recent advancements. Biomolecules, 9.","DOI":"10.3390\/biom9110735"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/s12276-020-0384-2","article-title":"ROS in cancer therapy: The bright side of the moon","volume":"52","author":"Perillo","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhuang, X.C., Chen, G.L., Liu, Y., Zhang, Y.L., and Guo, M.Q. (2021). New Lignanamides with antioxidant and anti-inflammatory activities screened out and identified from Warburgia ugandensis combining affinity Ultrafiltration LC-MS with SOD and XOD enzymes. Antioxidants, 10.","DOI":"10.3390\/antiox10030370"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/S0031-9422(03)00374-1","article-title":"Flavonol glycosides of Warburgia ugandensis leaves","volume":"64","author":"Manguro","year":"2003","journal-title":"Phytochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhuang, X.C., Zhang, Y.L., Chen, G.L., Liu, Y., Hu, X.L., Li, N., Wu, J.L., and Guo, M.Q. (2021). Identification of anti-inflammatory and anti-proliferative neolignanamides from Warburgia ugandensis employing multi-target affinity Ultrafiltration and LC-MS. Pharmaceuticals, 14.","DOI":"10.3390\/ph14040313"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"448","DOI":"10.5897\/JMPR2018.6626","article-title":"A review on the botanical aspects, phytochemical contents and pharmacological activities of Warburgia ugandensis","volume":"12","author":"Okello","year":"2018","journal-title":"J. Med. Plants Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3535","DOI":"10.1016\/0031-9422(90)85270-P","article-title":"A comparative study of the stem-bark drimane sesquiterpenes and leaf volatile oils of Warburgia ugandensis and W. stuhlmannii","volume":"29","author":"Kioy","year":"1990","journal-title":"Phytochemistry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1021\/np50009a008","article-title":"Potential anticancer agents. XVI. isolation of bicyclofarnesane sesquiterpenoids from Capsicodendron dinisii","volume":"43","author":"Mahmoud","year":"1980","journal-title":"J. Nat. Prod."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s13659-015-0083-1","article-title":"Antiproliferative triterpenoid saponins from Leptaulus citroides Baill. from the Madagascar Rain Forest","volume":"6","author":"Su","year":"2016","journal-title":"Nat. Prod. Bioprospect."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1016\/j.bmcl.2017.02.067","article-title":"Bioactive drimane sesquiterpenoids and aromatic glycosides from Cinnamosma fragrans","volume":"27","author":"He","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3844","DOI":"10.3390\/molecules14103844","article-title":"Ugandenial A, a new drimane-type sesquiterpenoid from Warburgia ugandensis","volume":"14","author":"Xu","year":"2009","journal-title":"Molecules"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18993","DOI":"10.3390\/molecules191118993","article-title":"Study on the cytotoxic activity of drimane sesquiterpenes and nordrimane compounds against cancer cell lines","volume":"19","author":"Montenegro","year":"2014","journal-title":"Molecules"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1002\/cmdc.201500360","article-title":"Synthetic and biological studies of sesquiterpene polygodial: Activity of 9-epipolygodial against drug-resistant cancer cells","volume":"10","author":"Dasari","year":"2015","journal-title":"ChemMedChem"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.cbi.2019.03.029","article-title":"Antigrowth activity and induction of apoptosis in human melanoma cells by Drymis winteri forst extract and its active components","volume":"305","author":"Russo","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"96","DOI":"10.21010\/ajtcam.v12i2.15","article-title":"Antiproliferation effects of selected Tanzania plants","volume":"12","author":"Choi","year":"2015","journal-title":"Afr. J. Tradit. Complement Altern. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6615","DOI":"10.5897\/JMPR11.160","article-title":"Vegetative propagation of Warburgia ugandensis Sprague: An important medicinal tree species in Eastern Africa","volume":"5","author":"Akwatulira","year":"2011","journal-title":"J. Med. Plants Res."},{"key":"ref_39","first-page":"12","article-title":"Bioassay-guided studies on the cytotoxic and in vitro trypanocidal activities of a sesquiterpene (Muzigadial) derived from a Ugandan medicinal plant (Warburgia ugandensis)","volume":"1","author":"Olila","year":"2001","journal-title":"Afr. Health Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11627-019-09961-x","article-title":"An efficient callus-based in vitro regeneration protocol for Warburgia Ugandensis Sprague, an important medicinal plant in Africa","volume":"55","author":"Zhang","year":"2019","journal-title":"Vitro Cell. Dev. Biol.-Plant"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.dnarep.2018.07.008","article-title":"Multiple functions of p27 in cell cycle, apoptosis, epigenetic modification and transcriptional regulation for the control of cell growth: A double-edged sword protein","volume":"69","author":"Abbastabar","year":"2018","journal-title":"DNA Repair"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1080\/15548627.2020.1831217","article-title":"CDKN1B\/p27 regulates autophagy via the control of Ragulator and MTOR activity in amino acid-deprived cells","volume":"16","author":"Nowosad","year":"2020","journal-title":"Autophagy"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Duan, Y., Pan, J., Chen, J., Zhu, D., Wang, J., Sun, X., Chen, L., and Wu, L. (2016). Soluble egg antigens of schistosoma japonicum induce senescence of activated hepatic stellate cells by activation of the FoxO3a\/SKP2\/P27 pathway. PLoS Neglect. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0005268"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4580","DOI":"10.1038\/onc.2015.524","article-title":"Caspases uncouple p27(Kip1) from cell cycle regulated degradation and abolish its ability to stimulate cell migration and invasion","volume":"35","author":"Podmirseg","year":"2016","journal-title":"Oncogene"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1002\/jcb.21765","article-title":"c-Myc represses FOXO3a-mediated transcription of the gene encoding the p27(Kip1) cyclin dependent kinase inhibitor","volume":"104","author":"Chandramohan","year":"2008","journal-title":"J. Cell. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.bbagrm.2014.03.013","article-title":"Myc and cell cycle control","volume":"1849","author":"Bretones","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3699","DOI":"10.1038\/sj.emboj.7601790","article-title":"Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation","volume":"26","author":"Nagel","year":"2007","journal-title":"EMBO J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1073\/pnas.0907904107","article-title":"miR-221 overexpression contributes to liver tumorigenesis","volume":"107","author":"Pineau","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9815","DOI":"10.1074\/jbc.M110.165977","article-title":"SKP2 oncogene is a direct MYC target gene and MYC down-regulates p27(KIP1) through SKP2 in human leukemia cells","volume":"286","author":"Bretones","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1101\/gad.827200","article-title":"Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression","volume":"14","author":"Ohh","year":"2000","journal-title":"Genes Dev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.canlet.2017.06.031","article-title":"p27(Kip1) and human cancers: A reappraisal of a still enigmatic protein","volume":"403","author":"Bencivenga","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3789","DOI":"10.1038\/onc.2012.556","article-title":"Various modes of cell death induced by DNA damage","volume":"32","author":"Surova","year":"2013","journal-title":"Oncogene"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.ccr.2006.08.015","article-title":"Reactive oxygen species in cancer cells: Live by the sword, die by the sword","volume":"10","author":"Schumacker","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Chiu, C.C., Haung, J.W., Chang, F.R., Huang, K.J., Huang, H.M., Huang, H.W., Chou, C.K., Wu, Y.C., and Chang, H.W. (2013). Golden berry-derived 4beta-hydroxywithanolide E for selectively killing oral cancer cells by generating ROS, DNA damage, and apoptotic pathways. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064739"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1111\/bph.13408","article-title":"Decursin enhances TRAIL-induced apoptosis through oxidative stress mediated- endoplasmic reticulum stress signalling in non-small cell lung cancers","volume":"173","author":"Kim","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1016\/j.freeradbiomed.2011.03.008","article-title":"Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2\/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs","volume":"50","author":"Tang","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_57","first-page":"7289","article-title":"Cisplatin induces apoptosis of A549 cells by downregulating peroxidase V","volume":"22","author":"Chen","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1186\/s12964-020-00653-3","article-title":"Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells","volume":"18","author":"Dong","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"38541","DOI":"10.1038\/srep38541","article-title":"Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells","volume":"6","author":"Srivastava","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.colsurfb.2016.02.011","article-title":"Vitamin E TPGS conjugated carbon nanotubes improved efficacy of docetaxel with safety for lung cancer treatment","volume":"141","author":"Singh","year":"2016","journal-title":"Colloid Surf. B-Biointerfaces"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3512","DOI":"10.1158\/0008-5472.CAN-06-3914","article-title":"Novel action of paclitaxel against cancer cells: Bystander effect mediated by reactive oxygen species","volume":"67","author":"Alexandre","year":"2007","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1111\/bph.14652","article-title":"Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of paclitaxel in non-small cell lung cancer cells via Nrf2 inhibition","volume":"176","author":"Chen","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.ccell.2018.05.010","article-title":"ROS promotes cancer cell survival through calcium signaling","volume":"33","author":"Reczek","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ccell.2018.03.022","article-title":"NRF2 and the Hallmarks of cancer","volume":"34","author":"Chapman","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.redox.2017.04.013","article-title":"Controversy about pharmacological modulation of Nrf2 for cancer therapy","volume":"12","author":"Milkovic","year":"2017","journal-title":"Redox Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.phrs.2015.09.009","article-title":"Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition","volume":"102","author":"Cortes","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/j.bbamcr.2011.05.001","article-title":"Bimodal regulation of FoxO3 by AKT and 14-3-3","volume":"1813","author":"Dobson","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"27511","DOI":"10.18632\/oncotarget.8484","article-title":"Crosstalk between the IGF-1R\/AKT\/mTORC1 pathway and the tumor suppressors p53 and p27 determines cisplatin sensitivity and limits the effectiveness of an IGF-1R pathway inhibitor","volume":"7","author":"Davaadelger","year":"2016","journal-title":"Oncotarget"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1101\/gad.12.22.3499","article-title":"Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization","volume":"12","author":"Diehl","year":"1998","journal-title":"Genes Dev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1128\/MCB.19.2.1346","article-title":"Cyclin D1 expression mediated by phosphatidylinositol 3-kinase through mTOR-p70(S6K)-independent signaling in growth factor-stimulated NIH 3T3 fibroblasts","volume":"19","author":"Takuwa","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrm3735","article-title":"Self-consumption: The interplay of autophagy and apoptosis","volume":"15","author":"Marino","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1091\/mbc.e13-10-0590","article-title":"Atmospheric gas plasma-induced ROS production activates TNF-ASK1 pathway for the induction of melanoma cancer cell apoptosis","volume":"25","author":"Ishaq","year":"2014","journal-title":"Mol. Biol. Cell."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/jebm.12001","article-title":"Effect of injection of brucea javanica oil emulsion plus chemoradiotherapy for lung cancer: A review of clinical evidence","volume":"5","author":"Nie","year":"2012","journal-title":"J. Evid. Based Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.bbrc.2017.10.042","article-title":"Luteoloside induces G0\/G1 arrest and pro-death autophagy through the ROS-mediated AKT\/mTOR\/p70S6K signalling pathway in human non-small cell lung cancer cell lines","volume":"494","author":"Zhou","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"378","DOI":"10.3109\/13880209.2013.837935","article-title":"The genus Warburgia: A review of its traditional uses and pharmacology","volume":"52","author":"Maroyi","year":"2014","journal-title":"Pharm. 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