Login Register Cart 0
Review Article

Targeting Cancer Stem Cells Pathways for the Effective Treatment of Cancer

Author(s): Ashish Ranjan Dwivedi, Amandeep Thakur, Vijay Kumar, Ira Skvortsova and Vinod Kumar*

Volume 21, Issue 3, 2020

Page: [258 - 278] Pages: 21

DOI: 10.2174/1389450120666190821160730

Price: $65

Abstract

Resistance to chemotherapy and relapse are major hurdles for the effective treatment of cancer. Major reason for this is a small sub population of cancer stem cells (CSCs) and its microenvironment. CSCs are critical driving force for several types of cancer, such as gastric, colon, breast and many more. Hence, for the complete eradication of cancer, it is necessary to develop therapeutic approaches that can specifically target CSCs. Chemical agents that target different proteins involved in CSC signaling pathways, either as single agent or simultaneously targeting two or more proteins have generated promising pre-clinical and clinical results. In the current review article, we have discussed various targets and cellular pathways that can be explored for the effective and complete eradication of CSCs. Some latest developments in the field of design, synthesis and screening of ligands to target cancer stem cells have been summarized in the current review article.

Keywords: Cancer stem cells, PI3K/AKT pathway, Wnt Pathway, hedgehog pathway, notch pathway, nuclear factor-kappa-B.

« Previous Next »
Graphical Abstract

[1]
Hu Y, Fu L. Targeting cancer stem cells: a new therapy to cure cancer patients. Am J Cancer Res 2012; 2(3): 340-56.
[PMID: 22679565]
[2]
Dang CV, Reddy EP, Shokat KM, Soucek L. Drugging the ‘undruggable’ cancer targets. Nat Rev Cancer 2017; 17(8): 502-8.
[http://dx.doi.org/10.1038/nrc.2017.36] [PMID: 28643779]
[3]
Chylewska A, Biedulska M, Sumczynski P, Makowski M. Metallopharmaceuticals in therapy-a new horizon for scientific research. Curr Med Chem 2018; 25(15): 1729-91.
[http://dx.doi.org/10.2174/0929867325666171206102501] [PMID: 29210637]
[4]
Castro J, Ribo M, Benito A, Vilanova M. Apoptin, A Versatile Protein with Selective Antitumor Activity. Curr Med Chem 2018; 25(30): 3540-59.
[http://dx.doi.org/10.2174/0929867325666180309112023] [PMID: 29521208]
[5]
Moltzahn FR, Volkmer J-P, Rottke D, Ackermann R. “Cancer stem cells”-lessons from Hercules to fight the Hydra. Urol Oncol 2008; 26(6): 581-9.
[http://dx.doi.org/10.1016/j.urolonc.2008.07.009] [PMID: 18818107]
[6]
Volkart PA, Bitencourt-Ferreira G, Souto AA, de Azevedo WF. Cyclin-dependent kinase 2 in cellular senescence and cancer. a structural and functional review. Curr Drug Targets 2019; 20(7): 716-26.
[http://dx.doi.org/10.2174/1389450120666181204165344] [PMID: 30516105]
[7]
La Porta CAM, Zapperi S. Complexity in cancer stem cells and tumor evolution: Toward precision medicine. Semin Cancer Biol 2017; 44: 3-9.
[http://dx.doi.org/10.1016/j.semcancer.2017.02.007] [PMID: 28254567]
[8]
Biava PM, Basevi M, Biggiero L, Borgonovo A, Borgonovo E, Burigana F. Cancer cell reprogramming: stem cell differentiation stage factors and an agent based model to optimize cancer treatment. Curr Pharm Biotechnol 2011; 12(2): 231-42.
[http://dx.doi.org/10.2174/138920111794295783] [PMID: 21044002]
[9]
Kumar B, Singh S, Skvortsova I, Kumar V. Promising targets in anti-cancer drug development: Recent updates. Curr Med Chem 2017; 24(42): 4729-52.
[PMID: 28393696]
[10]
Cabrera MC, Hollingsworth RE, Hurt EM. Cancer stem cell plasticity and tumor hierarchy. World J Stem Cells 2015; 7(1): 27-36.
[http://dx.doi.org/10.4252/wjsc.v7.i1.27] [PMID: 25621103]
[11]
Chen S, Huang EH. The colon cancer stem cell microenvironment holds keys to future cancer therapy. J Gastrointest Surg 2014; 18(5): 1040-8.
[http://dx.doi.org/10.1007/s11605-014-2497-1] [PMID: 24643495]
[12]
Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle 2007; 6(19): 2332-8.
[http://dx.doi.org/10.4161/cc.6.19.4914] [PMID: 17786053]
[13]
Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin 2013; 34(6): 732-40.
[http://dx.doi.org/10.1038/aps.2013.27] [PMID: 23685952]
[14]
Marusyk, A and Polyak, K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta Rev Cancer 2010; 1805(1): 105-17.
[http://dx.doi.org/10.1016/j.bbcan.2009.11.002]
[15]
Relation T, Dominici M, Horwitz EM. Concise review: an (im) penetrable shield: how the tumor microenvironment protects cancer stem cells. Stem Cells 2017; 35(5): 1123-30.
[http://dx.doi.org/10.1002/stem.2596] [PMID: 28207184]
[16]
Yoshida GJ, Saya H. Therapeutic strategies targeting cancer stem cells. Cancer Sci 2016; 107(1): 5-11.
[http://dx.doi.org/10.1111/cas.12817] [PMID: 26362755]
[17]
Agliano A, Calvo A, Box C. The challenge of targeting cancer stem cells to halt metastasis. Semin Cancer Biol 2017; 44: 25-42.
[http://dx.doi.org/10.1016/j.semcancer.2017.03.003] [PMID: 28323021]
[18]
Kumar B, Kumar R, Skvortsova I, Kumar V. Mechanisms of tubulin binding ligands to target cancer cells: updates on their therapeutic potential and clinical trials. Curr Cancer Drug Targets 2017; 17(4): 357-75.
[http://dx.doi.org/10.2174/1568009616666160928110818] [PMID: 27697026]
[19]
Alvarado-Kristensson M, Rosselló CA. The biology of the nuclear envelope and its implications in cancer biology. Int J Mol Sci 2019; 20(10): 2586.
[http://dx.doi.org/10.3390/ijms20102586] [PMID: 31137762]
[20]
Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53(1): 615-27.
[http://dx.doi.org/10.1146/annurev.med.53.082901.103929] [PMID: 11818492]
[21]
Liu Y, Wang X, Wang G, Yang Y, Yuan Y, Ouyang L. The past, present and future of potential small-molecule drugs targeting p53-MDM2/MDMX for cancer therapy. Eur J Med Chem 2019; 176: 92-104.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.018] [PMID: 31100649]
[22]
Levin NMB, Pintro VO, Bitencourt-Ferreira G, de Mattos BB, de Castro Silvério A, de Azevedo WF Jr. Development of CDK-targeted scoring functions for prediction of binding affinity. Biophys Chem 2018; 235: 1-8.
[http://dx.doi.org/10.1016/j.bpc.2018.01.004] [PMID: 29407904]
[23]
Pal B, Bayat-Mokhtari R, Li H, et al. Stem cell altruism may serve as a novel drug resistance mechanism in oral cancer 2016.
[http://dx.doi.org/10.1158/1538-7445.AM2016-251]
[24]
Scadden DT. The stem-cell niche as an entity of action. Nature 2006; 441(7097): 1075-9.
[http://dx.doi.org/10.1038/nature04957] [PMID: 16810242]
[25]
Borah A, Raveendran S, Rochani A, Maekawa T, Kumar DS. Targeting self-renewal pathways in cancer stem cells: clinical implications for cancer therapy. Oncogenesis 2015; 4(11)e177
[http://dx.doi.org/10.1038/oncsis.2015.35] [PMID: 26619402]
[26]
Kuhlmann JD, Hein L, Kurth I, Wimberger P, Dubrovska A. Targeting cancer stem cells: promises and challenges. Anticancer Agents Med Chem 2016; 16(1): 38-58.
[http://dx.doi.org/10.2174/1871520615666150716104152] [PMID: 26179271]
[27]
Tsang NY, Chik WI, Sze LP, Wang M-Z, Tsang SW, Zhang H-J. The Use of Naphthoquinones and Furano-naphthoquinones as Antiinvasive Agents. Curr Med Chem 2018; 25(38): 5007-56.
[http://dx.doi.org/10.2174/0929867324666171006131927] [PMID: 28990521]
[28]
Li W, Sun X. Recent advances in developing novel anti-cancer drugs targeting tumor hypoxic and acidic microenvironments. Recent Patents Anticancer Drug Discov 2018; 13(4): 455-68.
[http://dx.doi.org/10.2174/1574892813666180831102519] [PMID: 30173649]
[29]
Makena MR, Ranjan A, Thirumala V, Reddy A. Cancer stem cells: Road to therapeutic resistance and strategies to overcome resistance. Biochimi Biophys Acta (BBA)-Mol Basis Dis 2018.
[30]
Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8(8): 627-44.
[http://dx.doi.org/10.1038/nrd2926] [PMID: 19644473]
[31]
Li H, Zeng J, Shen K. PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer. Arch Gynecol Obstet 2014; 290(6): 1067-78.
[http://dx.doi.org/10.1007/s00404-014-3377-3] [PMID: 25086744]
[32]
Tapia O, Riquelme I, Leal P, et al. The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch 2014; 465(1): 25-33.
[http://dx.doi.org/10.1007/s00428-014-1588-4] [PMID: 24844205]
[33]
Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 2015; 15(1): 7-24.
[http://dx.doi.org/10.1038/nrc3860] [PMID: 25533673]
[34]
Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 2004; 30(2): 193-204.
[http://dx.doi.org/10.1016/j.ctrv.2003.07.007] [PMID: 15023437]
[35]
Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2(7): 489-501.
[http://dx.doi.org/10.1038/nrc839] [PMID: 12094235]
[36]
Yu JS, Cui W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development 2016; 143(17): 3050-60.
[http://dx.doi.org/10.1242/dev.137075] [PMID: 27578176]
[37]
Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296(5573): 1655-7.
[http://dx.doi.org/10.1126/science.296.5573.1655] [PMID: 12040186]
[38]
Martini M, Ciraolo E, Gulluni F, Hirsch E. Targeting PI3K in cancer: any good news? Front Oncol 2013; 3(108): 108.
[http://dx.doi.org/10.3389/fonc.2013.00108] [PMID: 23658859]
[39]
Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 2014; 13(2): 140-56.
[http://dx.doi.org/10.1038/nrd4204] [PMID: 24481312]
[40]
Saurat T, Buron F, Rodrigues N, et al. Design, synthesis, and biological activity of pyridopyrimidine scaffolds as novel PI3K/mTOR dual inhibitors. J Med Chem 2014; 57(3): 613-31.
[http://dx.doi.org/10.1021/jm401138v] [PMID: 24345273]
[41]
Cheng H, Li C, Bailey S, et al. Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04979064 through structure-based drug design. ACS Med Chem Lett 2012; 4(1): 91-7.
[http://dx.doi.org/10.1021/ml300309h] [PMID: 24900568]
[42]
Zhan M, Deng Y, Zhao L, et al. Design, synthesis, and biological evaluation of dimorpholine substituted thienopyrimidines as potential class I PI3K/mTOR dual inhibitors. J Med Chem 2017; 60(9): 4023-35.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00357] [PMID: 28409639]
[43]
Heffron TP, Ndubaku CO, Salphati L, et al. Discovery of clinical development candidate GDC-0084, a brain penetrant inhibitor of PI3K and mTOR. ACS Med Chem Lett 2016; 7(4): 351-6.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00005] [PMID: 27096040]
[44]
Takeuchi CS, Kim BG, Blazey CM, et al. Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR). J Med Chem 2013; 56(6): 2218-34.
[http://dx.doi.org/10.1021/jm3007933] [PMID: 23394126]
[45]
Mortensen DS, Perrin-Ninkovic SM, Shevlin G, et al. Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223. J Med Chem 2015; 58(13): 5323-33.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00626] [PMID: 26083478]
[46]
Mortensen DS, Perrin-Ninkovic SM, Shevlin G, et al. Optimization of a series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors and the discovery of CC-115. J Med Chem 2015; 58(14): 5599-608.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00627] [PMID: 26102506]
[47]
Heffron TP, Heald RA, Ndubaku C, et al. The rational design of selective benzoxazepin inhibitors of the α-isoform of phosphoinositide 3-kinase culminating in the identification of (s)-2-((2-(1-isopropyl-1h-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (gdc-0326). J Med Chem 2016; 59(3): 985-1002.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01483] [PMID: 26741947]
[48]
Zhang J-Q, Luo Y-J, Xiong Y-S, et al. Design, synthesis, and biological evaluation of substituted pyrimidines as potential phosphatidylinositol 3-kinase (pi3k) inhibitors. J Med Chem 2016; 59(15): 7268-74.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00235] [PMID: 27427973]
[49]
Ndubaku CO, Heffron TP, Staben ST, et al. Discovery of 2-3-[2-(1-isopropyl-3-methyl-1 h-1, 2–4-triazol-5-yl)-5, 6-dihydrobenzo [f] imidazo [1, 2-d][1, 4] oxazepin-9-yl]-1 h-pyrazol-1-yl-2-methylpropanamide (gdc-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem 2013; 56(11): 4597-610.
[http://dx.doi.org/10.1021/jm4003632] [PMID: 23662903]
[50]
Han F, Lin S, Liu P, et al. Discovery of a novel series of thienopyrimidine as highly potent and selective PI3K inhibitors. ACS Med Chem Lett 2015; 6(4): 434-8.
[http://dx.doi.org/10.1021/ml5005014] [PMID: 25893045]
[51]
Piddock RE, Loughran N, Marlein CR, et al. PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment. Blood Cancer J 2017; 7(3)e539
[http://dx.doi.org/10.1038/bcj.2017.16] [PMID: 28282033]
[52]
Ferguson FM, Ni J, Zhang T, et al. Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors. ACS Med Chem Lett 2016; 7(10): 908-12.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00209] [PMID: 27774127]
[53]
Evans CA, Liu T, Lescarbeau A, et al. Discovery of a selective phosphoinositide-3-kinase (PI3K)-γ inhibitor (IPI-549) as an immuno-oncology clinical candidate. ACS Med Chem Lett 2016; 7(9): 862-7.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00238] [PMID: 27660692]
[54]
Barlaam B, Cosulich S, Degorce S, et al. Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers. J Med Chem 2015; 58(2): 943-62.
[http://dx.doi.org/10.1021/jm501629p] [PMID: 25514658]
[55]
Morales GA, Garlich JR, Su J, et al. Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors. J Med Chem 2013; 56(5): 1922-39.
[http://dx.doi.org/10.1021/jm301522m] [PMID: 23410005]
[56]
Nusse R. Abstract IA01: Wnt signaling stem cell control and cancer. AACR 2016.
[57]
Miller JR, Hocking AM, Brown JD, Moon RT. Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways. Oncogene 1999; 18(55): 7860-72.
[http://dx.doi.org/10.1038/sj.onc.1203245] [PMID: 10630639]
[58]
Hawkins AG, Basrur V, da Veiga Leprevost F, et al. The ewing sarcoma secretome and its response to activation of Wnt/beta-catenin signaling. Mol Cell Proteomics 2018; 17(5): 901-12.
[http://dx.doi.org/10.1074/mcp.RA118.000596] [PMID: 29386236]
[59]
Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14(15): 1837-51.
[PMID: 10921899]
[60]
Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature 2005; 434(7035): 843-50.
[http://dx.doi.org/10.1038/nature03319] [PMID: 15829953]
[61]
Huang S-MA, Mishina YM, Liu S, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009; 461(7264): 614-20.
[http://dx.doi.org/10.1038/nature08356] [PMID: 19759537]
[62]
Hua Z, Bregman H, Buchanan JL, et al. Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors. J Med Chem 2013; 56(24): 10003-15.
[http://dx.doi.org/10.1021/jm401317z] [PMID: 24294969]
[63]
Larsson EA, Jansson A, Ng FM, et al. Fragment-based ligand design of novel potent inhibitors of tankyrases. J Med Chem 2013; 56(11): 4497-508.
[http://dx.doi.org/10.1021/jm400211f] [PMID: 23672613]
[64]
Shultz MD, Cheung AK, Kirby CA, et al. Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. J Med Chem 2013; 56(16): 6495-511.
[http://dx.doi.org/10.1021/jm400807n] [PMID: 23844574]
[65]
Liscio P, Carotti A, Asciutti S, et al. Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors. J Med Chem 2014; 57(6): 2807-12.
[http://dx.doi.org/10.1021/jm401356t] [PMID: 24527792]
[66]
Nathubhai A, Haikarainen T, Koivunen J, et al. Koumanov, Fo, Lloyd, MD, Holman, GD, Pihlajaniemi, T, Tosh, D, and Lehtiö, L. Highly potent and isoform selective dual site binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have antiproliferative activity. J Med Chem 2017; 60(2): 814-20.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01574] [PMID: 27983846]
[67]
Thomson DW, Wagner AJ, Bantscheff M, et al. Discovery of a highly selective Tankyrase inhibitor displaying growth inhibition effects against a diverse range of tumor derived cell lines. J Med Chem 2017; 60(13): 5455-71.
[68]
Soldi R, Horrigan SK, Cholody MW, et al. Design, synthesis, and biological evaluation of a series of anthracene-9, 10-dione dioxime β-catenin pathway inhibitors. J Med Chem 2015; 58(15): 5854-62.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00460] [PMID: 26182238]
[69]
Catrow JL, Zhang Y, Zhang M, Ji H. Discovery of selective small-molecule inhibitors for the β-Catenin/T-Cell factor protein–protein interaction through the optimization of the acyl hydrazone moiety. J Med Chem 2015; 58(11): 4678-92.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00223] [PMID: 25985283]
[70]
Mallinger A, Crumpler S, Pichowicz M, et al. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. J Med Chem 2015; 58(4): 1717-35.
[http://dx.doi.org/10.1021/jm501436m] [PMID: 25680029]
[71]
Czodrowski P, Mallinger A, Wienke D, et al. Structure-based optimization of potent, selective, and orally bioavailable cdk8 inhibitors discovered by high-throughput screening. J Med Chem 2016; 59(20): 9337-49.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00597] [PMID: 27490956]
[72]
Khatra H, Bose C, Sinha S. Discovery of hedgehog antagonists for cancer therapy. Curr Med Chem 2017; 24(19): 2033-58.
[http://dx.doi.org/10.2174/0929867324666170316115500] [PMID: 28302010]
[73]
Petrova R, Joyner AL. Roles for Hedgehog signaling in adult organ homeostasis and repair. Development 2014; 141(18): 3445-57.
[http://dx.doi.org/10.1242/dev.083691] [PMID: 25183867]
[74]
Velcheti V, Govindan R. Hedgehog signaling pathway and lung cancer. J Thorac Oncol 2007; 2(1): 7-10.
[http://dx.doi.org/10.1097/JTO.0b013e31802c0276] [PMID: 17410003]
[75]
Bale AE, Yu KP. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet 2001; 10(7): 757-62.
[http://dx.doi.org/10.1093/hmg/10.7.757] [PMID: 11257109]
[76]
Sheng T, Li C, Zhang X, et al. Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer 2004; 3(1): 29.
[http://dx.doi.org/10.1186/1476-4598-3-29] [PMID: 15482598]
[77]
Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003; 422(6929): 313-7.
[http://dx.doi.org/10.1038/nature01493] [PMID: 12629553]
[78]
Ji Z, Mei FC, Xie J, Cheng X. Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells. J Biol Chem 2007; 282(19): 14048-55.
[http://dx.doi.org/10.1074/jbc.M611089200] [PMID: 17353198]
[79]
Kubo M, Nakamura M, Tasaki A, et al. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 2004; 64(17): 6071-4.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-0416] [PMID: 15342389]
[80]
Steg AD, Bevis KS, Katre AA, et al. Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Cancer Res 2012; 18(3): 869-81.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-2188] [PMID: 22142828]
[81]
Al-Bahrani R, Nagamori S, Leng R, Petryk A, Sergi C. Differential expression of sonic hedgehog protein in human hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Pathol Oncol Res 2015; 21(4): 901-8.
[http://dx.doi.org/10.1007/s12253-015-9918-7] [PMID: 25740074]
[82]
Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009; 458(7239): 776-9.
[http://dx.doi.org/10.1038/nature07737] [PMID: 19169242]
[83]
Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo H-W. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers (Basel) 2016; 8(2): 22.
[http://dx.doi.org/10.3390/cancers8020022] [PMID: 26891329]
[84]
Cross S, Bury J. The Hedgehog signalling pathways in human pathology. Curr Diagn Pathol 2004; 10(2): 157-68.
[http://dx.doi.org/10.1016/j.cdip.2003.11.005]
[85]
Merchant AA, Matsui W. Targeting Hedgehog--a cancer stem cell pathway. Clin Cancer Res 2010; 16(12): 3130-40.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-2846] [PMID: 20530699]
[86]
Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol 2011; 27: 513-37.
[http://dx.doi.org/10.1146/annurev-cellbio-092910-154048] [PMID: 21801010]
[87]
Carpenter RL, Lo H-W. Hedgehog pathway and GLI1 isoforms in human cancer. Discov Med 2012; 13(69): 105-13.
[PMID: 22369969]
[88]
Johnson RW, Nguyen MP, Padalecki SS, et al. TGF-β promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res 2011; 71(3): 822-31.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2993] [PMID: 21189326]
[89]
Yu F-Y, Hong Y-Y, Qu J-F, Chen F, Li T-J. The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome. Int J Mol Med 2014; 34(2): 507-12.
[http://dx.doi.org/10.3892/ijmm.2014.1783] [PMID: 24840883]
[90]
Yoon JW, Gallant M, Lamm ML, et al. Noncanonical regulation of the Hedgehog mediator GLI1 by c-MYC in Burkitt lymphoma. Mol Cancer Res 2013; 11(6): 604-15.
[http://dx.doi.org/10.1158/1541-7786.MCR-12-0441] [PMID: 23525267]
[91]
Dahmane N, Sánchez P, Gitton Y, et al. The sonic hedgehog-gli pathway regulates dorsal brain growth and tumorigenesis. Development 2001; 128(24): 5201-12.
[PMID: 11748155]
[92]
Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 2015; 16(3): 225-38.
[http://dx.doi.org/10.1016/j.stem.2015.02.015] [PMID: 25748930]
[93]
Hanna A, Shevde LA. Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment. Mol Cancer 2016; 15(1): 24.
[http://dx.doi.org/10.1186/s12943-016-0509-3] [PMID: 26988232]
[94]
Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 2011; 8(2): 97-106.
[http://dx.doi.org/10.1038/nrclinonc.2010.196] [PMID: 21151206]
[95]
Zhang X, Tian Y, Yang Y, Hao J. Development of anticancer agents targeting the Hedgehog signaling. Cell Mol Life Sci 2017; 74(15): 2773-82.
[http://dx.doi.org/10.1007/s00018-017-2497-x] [PMID: 28314894]
[96]
Schaefer GI, Perez JR, Duvall JR, Stanton BZ, Shamji AF, Schreiber SL. Discovery of small-molecule modulators of the Sonic Hedgehog pathway. J Am Chem Soc 2013; 135(26): 9675-80.
[http://dx.doi.org/10.1021/ja400034k] [PMID: 23725514]
[97]
Ma H, Lu W, Sun Z, et al. Design, synthesis, and structure--activity-relationship of tetrahydrothiazolopyridine derivatives as potent smoothened antagonists. Eur J Med Chem 2015; 89: 721-32.
[http://dx.doi.org/10.1016/j.ejmech.2014.11.006] [PMID: 25462278]
[98]
Xin M, Wen J, Tang F, Tu C, Shen H, Zhao X. The discovery of novel N-(2-pyrimidinylamino) benzamide derivatives as potent hedgehog signaling pathway inhibitors. Bioorg Med Chem Lett 2013; 23(24): 6777-83.
[http://dx.doi.org/10.1016/j.bmcl.2013.10.022] [PMID: 24176396]
[99]
Xin M, Zhang L, Jin Q, et al. Discovery of novel 4-(2-pyrimidinylamino)benzamide derivatives as highly potent and orally available hedgehog signaling pathway inhibitors. Eur J Med Chem 2016; 110: 115-25.
[http://dx.doi.org/10.1016/j.ejmech.2016.01.018] [PMID: 26820554]
[100]
Xin M, Zhang L, Wen J, et al. Introduction of fluorine to phenyl group of 4-(2-pyrimidinylamino)benzamides leading to a series of potent hedgehog signaling pathway inhibitors. Bioorg Med Chem Lett 2017; 27(15): 3259-63.
[http://dx.doi.org/10.1016/j.bmcl.2017.06.030] [PMID: 28642101]
[101]
La Regina G, Bai R, Coluccia A, et al. New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer. J Med Chem 2014; 57(15): 6531-52.
[http://dx.doi.org/10.1021/jm500561a] [PMID: 25025991]
[102]
La Regina G, Bai R, Coluccia A, et al. New indole tubulin assembly inhibitors cause stable arrest of mitotic progression, enhanced stimulation of natural killer cell cytotoxic activity, and repression of hedgehog-dependent cancer. J Med Chem 2015; 58(15): 5789-807.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00310] [PMID: 26132075]
[103]
Bao X, Peng Y, Lu X, et al. Synthesis and evaluation of novel benzylphthalazine derivatives as hedgehog signaling pathway inhibitors. Bioorg Med Chem Lett 2016; 26(13): 3048-51.
[http://dx.doi.org/10.1016/j.bmcl.2016.05.009] [PMID: 27180012]
[104]
Alfonsi R, Botta B, Cacchi S, et al. Design, Palladium-Catalyzed Synthesis, and Biological Investigation of 2-Substituted 3-Aroylquinolin-4(1H)-ones as Inhibitors of the Hedgehog Signaling Pathway. J Med Chem 2017; 60(4): 1469-77.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01135] [PMID: 28122186]
[105]
Lu W, Liu Y, Ma H, et al. Design, synthesis, and structure-activity relationship of tetrahydropyrido[4,3-d]pyrimidine derivatives as potent smoothened antagonists with in vivo activity. ACS Chem Neurosci 2017; 8(9): 1980-94.
[http://dx.doi.org/10.1021/acschemneuro.7b00153] [PMID: 28618224]
[106]
Sjölund J, Manetopoulos C, Stockhausen M-T, Axelson H. The Notch pathway in cancer: differentiation gone awry. Eur J Cancer 2005; 41(17): 2620-9.
[http://dx.doi.org/10.1016/j.ejca.2005.06.025] [PMID: 16239105]
[107]
Basson MA. Signaling in cell differentiation and morphogenesis. Cold Spring Harb Perspect Biol 2012; 4(6)a008151
[http://dx.doi.org/10.1101/cshperspect.a008151] [PMID: 22570373]
[108]
Imayoshi I, Sakamoto M, Yamaguchi M, Mori K, Kageyama R. Essential roles of Notch signaling in maintenance of neural stem cells in developing and adult brains. J Neurosci 2010; 30(9): 3489-98.
[http://dx.doi.org/10.1523/JNEUROSCI.4987-09.2010] [PMID: 20203209]
[109]
Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 2009; 66(10): 1631-46.
[http://dx.doi.org/10.1007/s00018-009-8668-7] [PMID: 19165418]
[110]
Stylianou S, Clarke RB, Brennan K. Aberrant activation of notch signaling in human breast cancer. Cancer Res 2006; 66(3): 1517-25.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-3054] [PMID: 16452208]
[111]
Farnie G, Clarke RB. Mammary stem cells and breast cancer--role of Notch signalling. Stem Cell Rev 2007; 3(2): 169-75.
[http://dx.doi.org/10.1007/s12015-007-0023-5] [PMID: 17873349]
[112]
Aster JC, Pear WS, Blacklow SC. Notch signaling in leukemia. Annu. Rev. pathmechdis. Mech Dis 2008; 3: 587-613.
[113]
Hingorani SR, Petricoin EF III, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003; 4(6): 437-50.
[http://dx.doi.org/10.1016/S1535-6108(03)00309-X] [PMID: 14706336]
[114]
Collins BJ, Kleeberger W, Ball DW. Notch in lung development and lung cancerSemin Cancer Biol. Elsevier 2004.
[http://dx.doi.org/10.1016/j.semcancer.2004.04.015]
[115]
Hernandez SL, Banerjee D, Garcia A, et al. Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis. Vasc Cell 2013; 5(1): 17.
[http://dx.doi.org/10.1186/2045-824X-5-17] [PMID: 24066611]
[116]
Capaccione KM, Pine SR. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis 2013; 34(7): 1420-30.
[http://dx.doi.org/10.1093/carcin/bgt127] [PMID: 23585460]
[117]
Miele L. Notch signaling. Clin Cancer Res 2006; 12(4): 1074-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2570] [PMID: 16489059]
[118]
Andersson ER, Lendahl U. Therapeutic modulation of Notch signalling--are we there yet? Nat Rev Drug Discov 2014; 13(5): 357-78.
[http://dx.doi.org/10.1038/nrd4252] [PMID: 24781550]
[119]
Wang Z, Li Y, Banerjee S, Sarkar FH. Emerging role of Notch in stem cells and cancer. Cancer Lett 2009; 279(1): 8-12.
[http://dx.doi.org/10.1016/j.canlet.2008.09.030] [PMID: 19022563]
[120]
Zhou W, Wang G, Guo S. Regulation of angiogenesis via Notch signaling in breast cancer and cancer stem cells. Biochim Biophys Acta 2013; 1836(2): 304-20.
[PMID: 24183943]
[121]
Takebe N, Nguyen D, Yang SX. Targeting notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol Ther 2014; 141(2): 140-9.
[http://dx.doi.org/10.1016/j.pharmthera.2013.09.005] [PMID: 24076266]
[122]
Gavai AV, Quesnelle C, Norris D, et al. Discovery of clinical candidate BMS-906024: a potent pan-notch inhibitor for the treatment of leukemia and solid tumors. ACS Med Chem Lett 2015; 6(5): 523-7.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00001] [PMID: 26005526]
[123]
Shan W, Balog A, Quesnelle C, et al. BMS-871: a novel orally active pan-Notch inhibitor as an anticancer agent. Bioorg Med Chem Lett 2015; 25(9): 1905-9.
[http://dx.doi.org/10.1016/j.bmcl.2015.03.038] [PMID: 25857941]
[124]
Kerr G, Sheldon H, Chaikuad A, et al. A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis. Angiogenesis 2015; 18(2): 209-17.
[http://dx.doi.org/10.1007/s10456-014-9457-y] [PMID: 25557927]
[125]
Astudillo L, Da Silva TG, Wang Z, et al. The small molecule IMR-1 inhibits the notch transcriptional activation complex to suppress tumorigenesis. Cancer Res 2016; 76(12): 3593-603.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0061] [PMID: 27197169]
[126]
Wei J, Zhang L, Ren L, et al. Endosulfan inhibits proliferation through the Notch signaling pathway in human umbilical vein endothelial cells. Environ Pollut 2017; 221: 26-36.
[http://dx.doi.org/10.1016/j.envpol.2016.08.083] [PMID: 27939630]
[127]
Xu Y, Shu B, Tian Y, et al. Oleanolic acid induces osteosarcoma cell apoptosis by inhibition of Notch signaling. Mol Carcinog 2018; 57(7): 896-902.
[http://dx.doi.org/10.1002/mc.22810] [PMID: 29566282]
[128]
Massard C, Azaro A, Soria J-C, et al. First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer. Ann Oncol 2018; 29(9): 1911-7.
[http://dx.doi.org/10.1093/annonc/mdy244] [PMID: 30060061]
[129]
Dai G, Deng S, Guo W, et al. Notch pathway inhibition using DAPT, a γ-secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma. Mol Carcinog 2019; 58(1): 3-18.
[http://dx.doi.org/10.1002/mc.22873] [PMID: 29964327]
[130]
Quaglio D, Zhdanovskaya N, Tobajas G, et al. Chalcones and chalcone-mimetic derivatives as Notch inhibitors in a model of T-cell acute lymphoblastic leukemia. ACS Med Chem Lett 2019; 10(4): 639-43.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00608]
[131]
Dreesen O, Brivanlou AH. Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev 2007; 3(1): 7-17.
[http://dx.doi.org/10.1007/s12015-007-0004-8] [PMID: 17873377]
[132]
Rinkenbaugh, A and Baldwin, A. The NF-κB pathway and cancer stem cells. Cells 2016; 5(2): 16.
[http://dx.doi.org/10.3390/cells5020016]
[133]
Maldonado V, Meléndez-Zajgla J, Ortega A. Modulation of NF-κ B, and Bcl-2 in apoptosis induced by cisplatin in HeLa cells. Mutat Res 1997; 381(1): 67-75.
[http://dx.doi.org/10.1016/S0027-5107(97)00150-4] [PMID: 9403032]
[134]
Nakanishi C, Toi M. Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer 2005; 5(4): 297-309.
[http://dx.doi.org/10.1038/nrc1588] [PMID: 15803156]
[135]
Hamed MM, Darwish SS, Herrmann J, Abadi AH, Engel M. First bispecific inhibitors of the Epidermal Growth factor receptor kinase and the NF-κB activity as novel anti-cancer agents. J Med Chem 2017; 60(7): 2853-68.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01774] [PMID: 28291344]
[136]
Zhang L, Shi L, Soars SM, Kamps J, Yin H. Discovery of Novel Small-Molecule Inhibitors of NF-κB Signaling with Antiinflammatory and Anticancer Properties. J Med Chem 2018; 61(14): 5881-99.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01557] [PMID: 29870245]
[137]
Rana S, Blowers EC, Tebbe C, et al. Isatin derived spirocyclic analogues with α-methylene-γ-butyrolactone as anticancer agents: a structure–activity relationship study. J Med Chem 2016; 59(10): 5121-7.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00400] [PMID: 27077228]
[138]
Li N, Xin W-Y, Yao B-R. Cong W, Wang C-H, Hou G-G. N-phenylsulfonyl-3,5-bis(arylidene)-4-piperidone derivatives as activation NF-κB inhibitors in hepatic carcinoma cell lines. Eur J Med Chem 2018; 155: 531-44.
[http://dx.doi.org/10.1016/j.ejmech.2018.06.027] [PMID: 29909338]
[139]
Yao B-R, Sun Y, Chen S-L, et al. Dissymmetric pyridyl-substituted 3,5-bis(arylidene)-4-piperidones as anti-hepatoma agents by inhibiting NF-κB pathway activation. Eur J Med Chem 2019; 167: 187-99.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.020] [PMID: 30771605]

Rights & Permissions Print Cite
Article Metrics
261
5
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy