168
Views
17
CrossRef citations to date
0
Altmetric
Original Research

Leflunomide Inhibits Proliferation and Induces Apoptosis via Suppressing Autophagy and PI3K/Akt Signaling Pathway in Human Bladder Cancer Cells

, , ORCID Icon, , &
Pages 1897-1908 | Published online: 18 May 2020

References

  • KamatAM, HahnNM, EfstathiouJA, et al. Bladder cancer. Lancet (London, Engl). 2016;388(10061):2796–2810. doi:10.1016/S0140-6736(16)30512-8
  • DobruchJ, DaneshmandS, FischM, et al. Gender and bladder cancer: a collaborative review of etiology, biology, and outcomes. Eur Urol. 2016;69(2):300–310. doi:10.1016/j.eururo.2015.08.03726346676
  • RobertsonAG, KimJ, Al-AhmadieH, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540–556.e525. doi:10.1016/j.cell.2017.09.00728988769
  • AbufarajM, DalbagniG, DaneshmandS, et al. The role of surgery in metastatic bladder cancer: a systematic review. Eur Urol. 2017.
  • FuntSA, RosenbergJE. Systemic, perioperative management of muscle-invasive bladder cancer and future horizons. Nat Rev Clin Oncol. 2017;14(4):221–234. doi:10.1038/nrclinonc.2016.18827874062
  • MadakJT, BankheadA 3rd, CuthbertsonCR, ShowalterHD, NeamatiN. Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer. Pharmacol Ther. 2018.
  • KoundinyaM, SudhalterJ, CourjaudA, et al. Dependence on the pyrimidine biosynthetic enzyme DHODH is a synthetic lethal vulnerability in mutant KRAS-driven cancers. Cell Chem Biol. 2018;25(6):705–717.e711. doi:10.1016/j.chembiol.2018.03.00529628435
  • Mohamad FairusAK, ChoudharyB, HosahalliS, KavithaN, ShatrahO. Dihydroorotate dehydrogenase (DHODH) inhibitors affect ATP depletion, endogenous ROS and mediate S-phase arrest in breast cancer cells. Biochimie. 2017;135:154–163. doi:10.1016/j.biochi.2017.02.00328196676
  • ChenY, HuangQ, ZhouH, WangY, HuX, LiT. Inhibition of canonical WNT/beta-catenin signaling is involved in leflunomide (LEF)-mediated cytotoxic effects on renal carcinoma cells. Oncotarget. 2016;7(31):50401–50416. doi:10.18632/oncotarget.1040927391060
  • ChonWJ, JosephsonMA. Leflunomide in renal transplantation. Expert Rev Clin Immunol. 2011;7(3):273–281. doi:10.1586/eci.11.2021595593
  • TeschnerS, BurstV. Leflunomide: a drug with a potential beyond rheumatology. Immunotherapy. 2010;2(5):637–650. doi:10.2217/imt.10.5220874647
  • BreedveldFC, DayerJM. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000;59(11):841–849. doi:10.1136/ard.59.11.84111053058
  • HwangC, HeathEI. Angiogenesis inhibitors in the treatment of prostate cancer. J Hematol Oncol. 2010;3(1):26. doi:10.1186/1756-8722-3-2620678204
  • BahrHI, ToraihEA, MohammedEA, MohammadHM, AliEA, ZaitoneSA. Chemopreventive effect of leflunomide against Ehrlich’s solid tumor grown in mice: effect on EGF and EGFR expression and tumor proliferation. Life Sci. 2015;141:193–201. doi:10.1016/j.lfs.2015.10.00326439991
  • DoscasME, WilliamsonAJ, UshaL, et al. Inhibition of p70 S6 kinase (S6K1) activity by A77 1726 and its effect on cell proliferation and cell cycle progress. Neoplasia (New York, NY). 2014;16(10):824–834. doi:10.1016/j.neo.2014.08.006
  • KisE, NagyT, JaniM, et al. Leflunomide and its metabolite A771726 are high affinity substrates of BCRP: implications for drug resistance. Ann Rheum Dis. 2009;68(7):1201–1207. doi:10.1136/ard.2007.08626418397960
  • DietrichS, KramerOH, HahnE, et al. Leflunomide induces apoptosis in fludarabine-resistant and clinically refractory CLL cells. Clin Cancer Res. 2012;18(2):417–431. doi:10.1158/1078-0432.CCR-11-104922072733
  • HailN Jr., ChenP, BushmanLR. Teriflunomide (leflunomide) promotes cytostatic, antioxidant, and apoptotic effects in transformed prostate epithelial cells: evidence supporting a role for teriflunomide in prostate cancer chemoprevention. Neoplasia (New York, NY). 2010;12(6):464–475. doi:10.1593/neo.10168
  • AlhefdhiA, BurkeJF, RedlichA, KunnimalaiyaanM, ChenH. Leflunomide suppresses growth in human medullary thyroid cancer cells. J Surg Res. 2013;185(1):212–216. doi:10.1016/j.jss.2013.05.08923816245
  • BaumannP, Mandl-WeberS, VolklA, et al. Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells. Mol Cancer Ther. 2009;8(2):366–375. doi:10.1158/1535-7163.MCT-08-066419174558
  • ChuM, ZhangC. Inhibition of angiogenesis by leflunomide via targeting the soluble ephrin-A1/EphA2 system in bladder cancer. Sci Rep. 2018;8(1):1539. doi:10.1038/s41598-018-19788-y29367676
  • ChengL, WangH, GuoK, et al. Reversine, a substituted purine, exerts an inhibitive effect on human renal carcinoma cells via induction of cell apoptosis and polyploidy. Onco Targets Ther. 2018;11:1025–1035. doi:10.2147/OTT.S15819829520153
  • ThomeMP, Filippi-ChielaEC, VillodreES, et al. Ratiometric analysis of Acridine Orange staining in the study of acidic organelles and autophagy. J Cell Sci. 2016;129(24):4622–4632. doi:10.1242/jcs.19505727875278
  • EmerlingBM, AkcakanatA. Targeting PI3K/mTOR signaling in cancer. Cancer Res. 2011;71(24):7351–7359. doi:10.1158/0008-5472.CAN-11-169921987725
  • LinYC, LinJF, WenSI, et al. Inhibition of high basal level of autophagy induces apoptosis in human bladder cancer cells. J Urol. 2016;195(4 Pt 1):1126–1135. doi:10.1016/j.juro.2015.10.12826519656
  • LinJF, LinYC, YangSC, et al. Autophagy inhibition enhances RAD001-induced cytotoxicity in human bladder cancer cells. Drug Des Devel Ther. 2016;10:1501–1513. doi:10.2147/DDDT.S95900
  • LinJF, TsaiTF, LiaoPC, et al. Benzyl isothiocyanate induces protective autophagy in human prostate cancer cells via inhibition of mTOR signaling. Carcinogenesis. 2013;34(2):406–414. doi:10.1093/carcin/bgs35923172666
  • LiuX, ZhaoP, WangX, et al. Celastrol mediates autophagy and apoptosis via the ROS/JNK and Akt/mTOR signaling pathways in glioma cells. J Exp Clin Cancer Res. 2019;38(1):184. doi:10.1186/s13046-019-1173-431053160
  • KangM, JeongCW, KuJH, KwakC, KimHH. Inhibition of autophagy potentiates atorvastatin-induced apoptotic cell death in human bladder cancer cells in vitro. Int J Mol Sci. 2014;15(5):8106–8121. doi:10.3390/ijms1505810624815071
  • MadakJT, BankheadA 3rd, CuthbertsonCR, ShowalterHD, NeamatiN. Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer. Pharmacol Ther. 2019;195:111–131. doi:10.1016/j.pharmthera.2018.10.01230347213
  • HansonK, RobinsonSD, Al-YousufK, et al. The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth. Oncotarget. 2018;9(3):3815–3829. doi:10.18632/oncotarget.2337829423085
  • BrownKK, SpinelliJB, AsaraJM, TokerA. Adaptive reprogramming of de novo pyrimidine synthesis is a metabolic vulnerability in triple-negative breast cancer. Cancer Discov. 2017;7(4):391–399. doi:10.1158/2159-8290.CD-16-061128255083