Natural products as a means of overcoming cisplatin chemoresistance in bladder cancer

Abstract

Cisplatin remains an integral part of the treatment for muscle invasive bladder cancer. A large number of patients do not respond to cisplatin-based chemotherapy and efficacious salvage regimens are limited. Immunotherapy has offered a second line of treatment; however, only approximately 20% of patients respond, and molecular subtyping of tumors indicates there may be significant overlap in those patients that respond to cisplatin and those patients that respond to immunotherapy. As such, restoring sensitivity to cisplatin remains a major hurdle to improving patient care. One potential source of compounds for enhancing cisplatin is naturally derived bioactive products such as phytochemicals, flavonoids and others. These compounds can activate a diverse array of different pathways, many of which can directly promote or inhibit cisplatin sensitivity. The purpose of this review is to understand current drug development in the area of natural products and to assess how these compounds may enhance cisplatin treatment in bladder cancer patients.

Keywords

Cisplatin / bladder cancer / natural products / apoptosis

References

[1] Kamat AM,Efstathiou JA.Bladder cancer..Lancet2016;388:2796-810

[2] Penticuff JC,Sielecki TM,Taylor JA3rd.MIF family proteins in genitourinary cancer: tumorigenic roles and therapeutic potential..Nat Rev Urol2019;16:318-28

[3] Grossman HB,Tangen CM.Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer..N Engl J Med2003;349:859-66

[4] Scattoni V,Nava L.Five-year results of neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy plus radical cystectomy in locally advanced bladder cancer..Eur Urol1995;28:102-7

[5] Calabro F.Neoadjuvant and adjuvant chemotherapy in muscle-invasive bladder cancer..Eur Urol2009;55:348-58

[6] Calabro F.Localized and locally advanced bladder cancer..Curr Treat Options Oncol2002;3:413-28

[7] Anari F,Choi W.Neoadjuvant dose-dense gemcitabine and cisplatin in muscle-invasive bladder cancer: results of a phase 2 trial..Eur Urol Oncol2018;1:54-60 PMCID:PMC6226048

[8] Kurtova AV,Mo Q.Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance..Nature2015;517:209-13 PMCID:PMC4465385

[9] Pabla N.Cisplatin nephrotoxicity: mechanisms and renoprotective strategies..Kidney Int2008;73:994-1007

[10] Miller RP,Ramesh G.Mechanisms of cisplatin nephrotoxicity..Toxins (Basel)2010;2:2490-518 PMCID:PMC3153174

[11] Ridzuan NRA,Othman F,Hussan F.Protective role of natural products in cisplatin-induced nephrotoxicity..Mini Rev Med Chem2019;19:1134-43

[12] Demain AL.Natural products for cancer chemotherapy..Microb Biotechnol2011;4:687-99 PMCID:PMC3815406

[13] Siddik ZH.Cisplatin: mode of cytotoxic action and molecular basis of resistance..Oncogene2003;22:7265-79

[14] Galluzzi L,Vitale I.Molecular mechanisms of cisplatin resistance..Oncogene2012;31:1869-83

[15] Ishida S,Thiele DJ.Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals..Proc Natl Acad Sci U S A2002;99:14298-302 PMCID:PMC137878

[16] Song IS,Siddik ZH.Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells..Mol Cancer Ther2004;3:1543-9

[17] Eastman A.Glutathione-mediated activation of anticancer platinum(IV) complexes..Biochem Pharmacol1987;36:4177-8

[18] Eastman A.Interaction of trans-diamminedichloroplatinum(II) with DNA: formation of monofunctional adducts and their reaction with glutathione..Biochemistry1987;26:3303-7

[19] Eastman A.The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes..Pharmacol Ther1987;34:155-66

[20] Woods D.Chemotherapy induced DNA damage response: convergence of drugs and pathways..Cancer Biol Ther2013;14:379-89 PMCID:PMC3672181

[21] Sangster-Guity N,Papadopoulos N.ATR mediates cisplatin resistance in a p53 genotype-specific manner..Oncogene2011;30:2526-33 PMCID:PMC3107343

[22] Konstantakou EG,Karkoulis PK,Margaritis LH.Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses..Int J Oncol2009;35:401-16

[23] Bunz F,Torrance C.Disruption of p53 in human cancer cells alters the responses to therapeutic agents..J Clin Invest1999;104:263-9 PMCID:PMC408422

[24] Kramer G,Mertens HJ.Differentiation between cell death modes using measurements of different soluble forms of extracellular cytokeratin 18..Cancer Res2004;64:1751-6

[25] Sancho-Martinez SM,Cannata-Andia JB,Lopez-Hernandez FJ.Necrotic concentrations of cisplatin activate the apoptotic machinery but inhibit effector caspases and interfere with the execution of apoptosis..Toxicol Sci2011;122:73-85

[26] Jaeschke H.Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury..Gastroenterology2003;125:1246-57

[27] Hernandez C,Schwabe RF.Damage-associated molecular patterns in cancer: a double-edged sword..Oncogene2016;35:5931-41 PMCID:PMC5119456

[28] Luedde T,Schwabe RF.Cell death and cell death responses in liver disease: mechanisms and clinical relevance..Gastroenterology2014;147:765-83.e4 PMCID:PMC4531834

[29] Galsky MD,Hahn NM.Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes..Eur Urol2018;73:751-9

[30] Kilari D,Pandya C.Copper transporter-CTR1 expression and pathological outcomes in platinum-treated muscle-invasive bladder cancer patients..Anticancer Res2016;36:495-501

[31] Perde-Schrepler M,Virag P.The expression of copper transporters associated with the ototoxicity induced by platinum-based chemotherapeutic agents..Hear Res2020;388:107893

[32] Katano K,Safaei R.Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper..Cancer Res2002;62:6559-65

[33] Wang L,Zhang Z.Progress and prospects of reactive oxygen species in metal carcinogenesis..Curr Pharmacol Rep2016;2:178-86 PMCID:PMC5015764

[34] Huang CF,Ma SR.Clinical significance of Keap1 and Nrf2 in oral squamous cell carcinoma..PLoS One2013;8:e83479 PMCID:PMC3873935

[35] Wang XJ,Villeneuve NF.Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2..Carcinogenesis2008;29:1235-43 PMCID:PMC3312612

[36] Godwin AK,O’Dwyer PJ,Hamilton TC.High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis..Proc Natl Acad Sci U S A1992;89:3070-4 PMCID:PMC48805

[37] Bakka A,Johnsen AB,Rugstad HE.Resistance against cis-dichlorodiammineplatinum in cultured cells with a high content of metallothionein..Toxicol Appl Pharmacol1981;61:215-26

[38] Miyajima A,Yoshioka K,Tazaki H.Role of reactive oxygen species in cis-dichlorodiammineplatinum-induced cytotoxicity on bladder cancer cells..Br J Cancer1997;76:206-10 PMCID:PMC2223948

[39] Miyajima A,Tachibana M,Hayakawa M.N-acetylcysteine modifies cis-dichlorodiammineplatinum-induced effects in bladder cancer cells..Jpn J Cancer Res1999;90:565-70 PMCID:PMC5926102

[40] Lee JS.Nrf2 as a novel molecular target for chemoprevention..Cancer Lett2005;224:171-84

[41] Kitamura H.NRF2 addiction in cancer cells..Cancer Sci2018;109:900-11 PMCID:PMC5891176

[42] Van Allen EM,Kim P.Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma..Cancer Discov2014;4:1140-53 PMCID:PMC4238969

[43] Hanawalt PC.Transcription-coupled DNA repair: two decades of progress and surprises..Nat Rev Mol Cell Biol2008;9:958-70

[44] Li Q,Frazier Z.ERCC2 helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle-invasive bladder cancer..Clin Cancer Res2019;25:977-88 PMCID:PMC6434536

[45] Ozcan MF,Dincer N.Low ERCC1 expression is associated with prolonged survival in patients with bladder cancer receiving platinum-based neoadjuvant chemotherapy..Urol Oncol2013;31:1709-15

[46] Mbeutcha A,Margulis V.Prognostic role of ERCC1 protein expression in upper tract urothelial carcinoma following radical nephroureterectomy with curative intent..World J Urol2016;34:1155-61

[47] Klatte T,Rink M.ERCC1 as a prognostic and predictive biomarker for urothelial carcinoma of the bladder following radical cystectomy..J Urol2015;194:1456-62

[48] Kawashima A,Tsujimura A.A review of ERCC1 gene in bladder cancer: implications for carcinogenesis and resistance to chemoradiotherapy..Adv Urol2012;2012:812398 PMCID:PMC3205704

[49] Kawashima A,Kakuta Y.Excision repair cross-complementing group 1 may predict the efficacy of chemoradiation therapy for muscle-invasive bladder cancer..Clin Cancer Res2011;17:2561-9

[50] Sun JM,Park SH.ERCC1 as a biomarker for bladder cancer patients likely to benefit from adjuvant chemotherapy..BMC Cancer2012;12:187 PMCID:PMC3404914

[51] Kelley MR,Guo C.Identification and characterization of new chemical entities targeting apurinic/apyrimidinic endonuclease 1 for the prevention of chemotherapy-induced peripheral neuropathy..J Pharmacol Exp Ther2016;359:300-9 PMCID:PMC5074487

[52] Shah F,Messmann RA,Fishel ML.Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic..NPJ Precis Oncol2017;1: PMCID:PMC5558897

[53] Fishel ML,McGeown J.Antitumor activity and mechanistic characterization of APE1/Ref-1 inhibitors in bladder cancer..Mol Cancer Ther2019;18:1947-60 PMCID:PMC6844258

[54] Fishel ML,Devlin CM.Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1) redox function negatively regulates NRF2..J Biol Chem2015;290:3057-68 PMCID:PMC4317024

[55] Sawant A,Dangeti M,Sobol RW.Differential role of base excision repair proteins in mediating cisplatin cytotoxicity..DNA Repair (Amst)2017;51:46-59 PMCID:PMC5328804

[56] Warburg O.On the origin of cancer cells..Science1956;123:309-14

[57] Vander Heiden MG,Thompson CB.Understanding the Warburg effect: the metabolic requirements of cell proliferation..Science2009;324:1029-33 PMCID:PMC2849637

[58] Woolbright BL,Harris RA.Metabolic flexibility in cancer: targeting the pyruvate dehydrogenase kinase:pyruvate dehydrogenase axis..Mol Cancer Ther2019;18:1673-81

[59] Wang X,Wu XR.Inhibition of pyruvate kinase M2 markedly reduces chemoresistance of advanced bladder cancer to cisplatin..Sci Rep2017;7:45983 PMCID:PMC5380992

[60] Woolbright BL,Mikhalyuk A.The role of pyruvate dehydrogenase kinase-4 (PDK4) in bladder cancer and chemoresistance..Mol Cancer Ther2018;17:2004-12 PMCID:PMC6724734

[61] Bonnet S,Allalunis-Turner J.A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth..Cancer Cell2007;11:37-51

[62] Liu W,Pirani K.Tumor M2-PK: a novel urine marker of bladder cancer..PLoS One2019;14:e0218737 PMCID:PMC6597081

[63] Michaud WA,Mroz EA.Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma..Clin Cancer Res2009;15:1645-54 PMCID:PMC2745309

[64] Yan D,Kuo MT.C-Jun N-terminal kinase signalling pathway in response to cisplatin..J Cell Mol Med2016;20:2013-9 PMCID:PMC5082413

[65] Oh CJ,Choi YK.Pyruvate dehydrogenase kinase 4 deficiency attenuates cisplatin-induced acute kidney injury..Kidney Int2017;91:880-95

[66] Zargar H,Lotan Y.Final pathological stage after neoadjuvant chemotherapy and radical cystectomy for bladder cancer-does pT0 predict better survival than pTa/Tis/T1?.J Urol2016;195:886-93

[67] Zargar-Shoshtari K,Dinney CP.Clinical and therapeutic factors associated with adverse pathological outcomes in clinically node-negative patients treated with neoadjuvant cisplatin-based chemotherapy and radical cystectomy..World J Urol2016;34:695-701

[68] Robertson AG,Al-Ahmadie H.Comprehensive molecular characterization of muscle-invasive bladder cancer..Cell2017;171:540-56.e25 PMCID:PMC5687509

[69] McConkey DJ,Shen Y.A prognostic gene expression signature in the molecular classification of chemotherapy-naive urothelial cancer is predictive of clinical outcomes from neoadjuvant chemotherapy: a phase 2 trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with bevacizumab in urothelial cancer..Eur Urol2016;69:855-62 PMCID:PMC4775435

[70] McConkey DJ,Dinney CP.Genetic subtypes of invasive bladder cancer..Curr Opin Urol2015;25:449-58

[71] Choi W,Ochoa A.Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer..Nat Rev Urol2014;11:400-10

[72] Dyrskjot L.Molecular subtypes of bladder cancer: academic exercise or clinical relevance?.Eur Urol2019;75:433-4

[73] Thomsen MBH,Lamy P.Comprehensive multiregional analysis of molecular heterogeneity in bladder cancer..Sci Rep2017;7:11702 PMCID:PMC5600970

[74] Hedegaard J,Nordentoft I.Comprehensive transcriptional analysis of early-stage urothelial carcinoma..Cancer Cell2016;30:27-42

[75] Sjodahl G,Liedberg F.Molecular classification of urothelial carcinoma: global mRNA classification versus tumour-cell phenotype classification..J Pathol2017;242:113-25 PMCID:PMC5413843

[76] Grivas P,Alva AS.Validation of a neuroendocrine-like classifier confirms poor outcomes in patients with bladder cancer treated with cisplatin-based neoadjuvant chemotherapy..Urol Oncol2020;38:262-8

[77] Batista da Costa J,Bivalacqua TJ.Molecular characterization of neuroendocrine-like bladder cancer..Clin Cancer Res2019;25:3908-20

[78] de Oliveira Junior RG,da Silva Almeida JRG,Thiery V.Sensitization of tumor cells to chemotherapy by natural products: a systematic review of preclinical data and molecular mechanisms..Fitoterapia2018;129:383-400

[79] Kotecha R,Espinoza JL.Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence..Oncotarget2016;7:52517-29 PMCID:PMC5239570

[80] Singh S,Kanwar SS.Lead phytochemicals for anticancer drug development..Front Plant Sci2016;7:1667 PMCID:PMC5099879

[81] Vinod BS,Anto RJ.Phytochemicals as chemosensitizers: from molecular mechanism to clinical significance..Antioxid Redox Signal2013;18:1307-48

[82] Wang H,Shu L.Plants vs. cancer: a review on natural phytochemicals in preventing and treating cancers and their druggability..Anticancer Agents Med Chem2012;12:1281-305 PMCID:PMC4017674

[83] Schopf FH,Buchner J.The HSP90 chaperone machinery..Nat Rev Mol Cell Biol2017;18:345-60

[84] Khandelwal A,Balch M.Structure-guided design of an Hsp90beta N-terminal isoform-selective inhibitor..Nat Commun2018;9:425 PMCID:PMC5789826

[85] Garg G,Zhao H.Development of phenyl cyclohexylcarboxamides as a novel class of Hsp90 C-terminal inhibitors..Chemistry2017;23:16574-85 PMCID:PMC5724527

[86] Whitesell L,Falsey R.The stress response: implications for the clinical development of hsp90 inhibitors..Curr Cancer Drug Targets2003;3:349-58

[87] Marcu MG,Bouhouche I,Neckers LM.The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone..J Biol Chem2000;275:37181-6

[88] Tatokoro M,Yoshida S.Potential role of Hsp90 inhibitors in overcoming cisplatin resistance of bladder cancer-initiating cells..Int J Cancer2012;131:987-96 PMCID:PMC7447157

[89] Abotaleb M,Varghese E.Flavonoids in cancer and apoptosis..Cancers (Basel)2018;11:

[90] Singh AV,Blackburn GL.Soy phytochemicals prevent orthotopic growth and metastasis of bladder cancer in mice by alterations of cancer cell proliferation and apoptosis and tumor angiogenesis..Cancer Res2006;66:1851-8 PMCID:PMC2683370

[91] Kuiper GG,Carlsson B.Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta..Endocrinology1998;139:4252-63

[92] Hoffman KL,Smith CL.Raloxifene inhibits growth of RT4 urothelial carcinoma cells via estrogen receptor-dependent induction of apoptosis and inhibition of proliferation..Horm Cancer2013;4:24-35 PMCID:PMC3541450

[93] McGrath M,De Vivo I.Hormonal and reproductive factors and the risk of bladder cancer in women..Am J Epidemiol2006;163:236-44

[94] Daugherty SE,Pfeiffer RM,Hoover RN.Reproductive factors and menopausal hormone therapy and bladder cancer risk in the NIH-AARP Diet and Health Study..Int J Cancer2013;133:462-72 PMCID:PMC3646919

[95] Lin JJ,Su YL.Proteomics analysis of tangeretin-induced apoptosis through mitochondrial dysfunction in bladder cancer cells..Int J Mol Sci2019;20: PMCID:PMC6429142

[96] Dong Y,Shi J.Tangeretin, a citrus polymethoxyflavonoid, induces apoptosis of human gastric cancer AGS cells through extrinsic and intrinsic signaling pathways..Oncol Rep2014;31:1788-94

[97] Liu VM.The role of pyruvate kinase M2 in cancer metabolism..Brain Pathol2015;25:781-3

[98] Wang Y,Nan Y.PKM2 inhibitor shikonin overcomes the cisplatin resistance in bladder cancer by inducing necroptosis..Int J Biol Sci2018;14:1883-91 PMCID:PMC6231221

[99] Ning X,Li R.Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase..Eur J Med Chem2017;138:343-52

[100] Vander Heiden MG,Schuman E.Identification of small molecule inhibitors of pyruvate kinase M2..Biochem Pharmacol2010;79:1118-24 PMCID:PMC2823991

[101] Lamm DL,Hale K.Bladder cancer: current optimal intravesical treatment..Urol Nurs2005;25:323-631-2

[102] Onrust SV,Goa KL.Epirubicin: a review of its intravesical use in superficial bladder cancer..Drugs Aging1999;15:307-33

[103] Tozawa K,Yamada Y,Sasaki S.Prevention of the recurrence of superficial bladder cancers: intravesical instillation of bacillus calmette-guerin versus bacillus calmette-guerin plus epirubicin..Asian Pac J Cancer Prev2000;1:217-20

[104] Melekos MD,Paranychianakis GS.Intravesical 4’-epi-doxorubicin (epirubicin) versus bacillus Calmette-Guerin. A controlled prospective study on the prophylaxis of superficial bladder cancer..Cancer1993;72:1749-55

[105] Melekos MD,Pantazakos A,Paranychianakis G.Intravesical bacillus Calmette-Guerin immunoprophylaxis of superficial bladder cancer: results of a controlled prospective trial with modified treatment schedule..J Urol1993;149:744-8

[106] Melekos MD,Fokaefs E.Intravesical instillations of 4-epi-doxorubicin (epirubicin) in the prophylactic treatment of superficial bladder cancer: results of a controlled prospective study..J Urol1992;147:371-5

[107] Hevener K,Lutat KE,Mooney JW.Recent developments in topoisomerase-targeted cancer chemotherapy..Acta Pharm Sin B2018;8:844-61 PMCID:PMC6251812

[108] Pan X,Hartley JA,Wang Z.Evodiamine, a dual catalytic inhibitor of type I and II topoisomerases, exhibits enhanced inhibition against camptothecin resistant cells..Phytomedicine2012;19:618-24

[109] Zhang T,Shi Q,Jin X.Evodiamine induces apoptosis and enhances TRAIL-induced apoptosis in human bladder cancer cells through mTOR/S6K1-mediated downregulation of Mcl-1..Int J Mol Sci2014;15:3154-71 PMCID:PMC3958903

[110] Riggs DR,Lamm DL.Allium sativum (garlic) treatment for murine transitional cell carcinoma..Cancer1997;79:1987-94

[111] Wang YB,Zheng XY,Yang K.Diallyl trisulfide induces Bcl-2 and caspase-3-dependent apoptosis via downregulation of Akt phosphorylation in human T24 bladder cancer cells..Phytomedicine2010;17:363-8

[112] Kim WT,Byun YJ.Garlic extract in bladder cancer prevention: evidence from T24 bladder cancer cell xenograft model, tissue microarray, and gene network analysis..Int J Oncol2017;51:204-12

[113] Shin DY,Kim GY,Choi YH.Inhibiting invasion into human bladder carcinoma 5637 cells with diallyl trisulfide by inhibiting matrix metalloproteinase activities and tightening tight junctions..Int J Mol Sci2013;14:19911-22 PMCID:PMC3821593

[114] Kuo CH,Wang TH.A novel DNA repair inhibitor, diallyl disulfide (DADS), impairs DNA resection during DNA double-strand break repair by reducing Sae2 and Exo1 levels..DNA Repair (Amst)2019;82:102690

[115] Ling H,He J,Jiang H.Diallyl disulfide selectively causes checkpoint kinase-1 mediated G2/M arrest in human MGC803 gastric cancer cell line..Oncol Rep2014;32:2274-82

[116] Jiang XY,Xu HY.Diallyl trisulfide suppresses tumor growth through the attenuation of Nrf2/Akt and activation of p38/JNK and potentiates cisplatin efficacy in gastric cancer treatment..Acta Pharmacol Sin2017;38:1048-58 PMCID:PMC5519247

[117] Tian B,Zhao Y.Effects of curcumin on bladder cancer cells and development of urothelial tumors in a rat bladder carcinogenesis model..Cancer Lett2008;264:299-308

[118] Sharma RA,Platton SL.Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance..Clin Cancer Res2004;10:6847-54

[119] Plummer SM,Manson MM.Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex..Oncogene1999;18:6013-20

[120] Mohammed SI,Abraham S.Cyclooxygenase inhibitors in urinary bladder cancer: in vitro and in vivo effects..Mol Cancer Ther2006;5:329-36

[121] Mizutani Y,Li YN,Kawauchi A.Enhanced sensitivity of bladder cancer cells to cisplatin mediated cytotoxicity and apoptosis in vitro and in vivo by the selective cyclooxygenase-2 inhibitor JTE-522..J Urol2004;172:1474-9

[122] Mohseni H,McFadden D,Jackson BJ.COX-2 inhibition demonstrates potent anti-proliferative effects on bladder cancer in vitro..J Surg Res2004;119:138-42

[123] Woolbright BL,Taylor JA3rd.Prostaglandin E2 as a therapeutic target in bladder cancer: From basic science to clinical trials..Prostaglandins Other Lipid Mediat2020;148:106409

[124] Liang Z,Mao J,Qian H.Curcumin reversed chronic tobacco smoke exposure induced urocystic EMT and acquisition of cancer stem cells properties via Wnt/beta-catenin..Cell Death Dis2017;8:e3066 PMCID:PMC5680574

[125] Li Y,Yang Z.Bladder cancer stem cells: clonal origin and therapeutic perspectives..Oncotarget2017;8:66668-79 PMCID:PMC5630446

[126] Kamat AM,Aggarwal BB.Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of nuclear factor-kappaB and nuclear factor-kappaB-regulated gene products in IFN-alpha-sensitive and IFN-alpha-resistant human bladder cancer cells..Mol Cancer Ther2007;6:1022-30

[127] Park BH,Jeon HG.Curcumin potentiates antitumor activity of cisplatin in bladder cancer cell lines via ROS-mediated activation of ERK1/2..Oncotarget2016;7:63870-86 PMCID:PMC5325410

[128] Sharma RA,Hill KA.Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer..Clin Cancer Res2001;7:1894-900

[129] Ireson C,Jones DJ.Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production..Cancer Res2001;61:1058-64

[130] Hoffer LJ,Assouline S.Phase I clinical trial of i.v. ascorbic acid in advanced malignancy..Ann Oncol2008;19:1969-74

[131] Padayatty SJ,Wang Y.Vitamin C pharmacokinetics: implications for oral and intravenous use..Ann Intern Med2004;140:533-7

[132] Ma Y,Levine M,Drisko J.High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy..Sci Transl Med2014;6:222ra18

[133] Parrow NL,Levine M.Parenteral ascorbate as a cancer therapeutic: a reassessment based on pharmacokinetics..Antioxid Redox Signal2013;19:2141-56 PMCID:PMC3869468

[134] Campbell EJ,Bozonet S,Robinson BA.Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice..Cancer Med2015;4:303-14 PMCID:PMC4329013

[135] Peng D,Gong Y.Vitamin C increases 5-hydroxymethylcytosine level and inhibits the growth of bladder cancer..Clin Epigenetics2018;10:94 PMCID:PMC6045833

[136] Witlox WJA,Brinkman M.An inverse association between the Mediterranean diet and bladder cancer risk: a pooled analysis of 13 cohort studies..Eur J Nutr2020;59:287-96 PMCID:PMC7000493

[137] Buckland G,Roswall N.Adherence to the Mediterranean diet and risk of bladder cancer in the EPIC cohort study..Int J Cancer2014;134:2504-11

[138] Ferro M,Buonerba C.Modified Glasgow Prognostic Score Is Associated With Risk Of Recurrence In Bladder Cancer Patients After Radical Cystectomy: a Multicenter Experience..Medicine (Baltimore)2015;94:e1861 PMCID:PMC4620818

[139] Sui X,Chen L,Li X.Inflammatory microenvironment in the initiation and progression of bladder cancer..Oncotarget2017;8:93279-94 PMCID:PMC5696263

[140] Lamm DL.Enhanced immunocompetence by garlic: role in bladder cancer and other malignancies..J Nutr2001;131:1067S-70