review therapeutic targeting of hypoxia and hypoxia inducible factors in cancer

    Review: Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer Caroline Wigerup, Sven P˚ahlman, Daniel Bexell PII: DOI: Reference: S0163-7258(16)30055-9 doi: 10.1016/j.pharmthera.2016.04.009 JPT 6901 To appear in: Pharmacology and Therapeutics Please cite this article as: Wigerup, C., P˚ ahlman, S & Bexell, D., Review: Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer, Pharmacology and Therapeutics (2016), doi: 10.1016/j.pharmthera.2016.04.009 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT P&T 22787 PT Review: Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer Translational Cancer Research, Medicon Village 404:C3, Lund University, Lund, Sweden cancer, hypoxia, hypoxia-inducible (HIF), neuroblastoma, AC CE P TE D pheochromocytoma, paraganglioma factor MA Keywords: NU SC RI Caroline Wigerup1, Sven Påhlman1 and Daniel Bexell1 Corresponding author: Sven Påhlman Translational Cancer Research Medicon Village 404:C3 Lund University SE-223 81 Lund, Sweden E-mail: sven.pahlman@med.lu.se ACCEPTED MANUSCRIPT Abstract Insufficient tissue oxygenation, or hypoxia, contributes to tumor aggressiveness and has a PT profound impact on clinical outcomes in cancer patients At decreased oxygen tensions, hypoxia-inducible factors (HIFs) and are stabilized and mediate a hypoxic response, RI primarily by acting as transcription factors HIFs exert differential effects on tumor growth SC and affect important cancer hallmarks including cell proliferation, apoptosis, differentiation, NU vascularization/angiogenesis, genetic instability, tumor metabolism, tumor immune responses, and invasion and metastasis As a consequence, HIFs mediate resistance to chemo- and MA radiotherapy and are associated with poor prognosis in cancer patients Intriguingly, perivascular tumor cells can also express HIF-2α, thereby forming a “pseudohypoxic” D phenotype that further contributes to tumor aggressiveness Therefore, therapeutic targeting of TE HIFs in cancer has the potential to improve treatment efficacy Different strategies to target hypoxic cancer cells and/or HIFs include hypoxia-activated prodrugs and inhibition of HIF AC CE P dimerization, mRNA or protein expression, DNA binding capacity, and transcriptional activity Here we review the functions of HIFs in the progression and treatment of malignant solid tumors We also highlight how HIFs may be targeted to improve the management of patients with therapy-resistant and metastatic cancer ACCEPTED MANUSCRIPT Abbreviations 2-methoxyestradiol (2ME2); amphotericin B (AmB); cancer stem cell (CSC); carbonic PT anhydrase IX (CAIX); clear cell renal cell carcinoma (ccRCC); dichloroacetic acid (DCA); erythropoietin (EPO); geldanamycin (GA); genetically engineered mouse models (GEMMs); RI factor inhibiting HIF-1 (FIH-1); heat shock protein (Hsp); histone deacetylase (HDAC); SC hypoxia-inducible factor (HIF); hypoxia responsive element (HRE); ionizing radiation, (IR); iron-responsive element (IRE); patient-derived xenografts (PDXs); polyethylene glycol prolyl-4-hydroxylases (PHDs); reactive oxygen NU (PEG); species (ROS); succinate MA dehydrogenase (SDH); sympathetic nervous system (SNS); transactivation domains (TADs); vascular endothelial growth factor (VEGF); von Hippel Lindau (VHL) Contents AC CE P TE D Introduction HIF regulation and function Hypoxia and HIFs in cancer 3.1 Measuring tumor hypoxia 3.2 Patient prognosis 3.3 Tumor cell viability 3.4 Tumor angiogenesis 3.5 Cancer stem cells 3.6 Metabolic reprogramming 3.7 Tumor immune response 3.8 Genomic instability 3.9 Tumor cell invasion and metastasis 3.10 Treatment resistance Targeting hypoxia and HIFs in cancer 4.1 Hypoxia-activated prodrugs 4.2 Drugs targeting hypoxic signaling 4.2.1 Inhibitors of HIF mRNA or protein expression 4.2.2 Inhibitors of HIF dimerization 4.2.3 Inhibitors of HIF-DNA binding 4.2.4 Inhibitors of HIF transcriptional activity Neural crest-derived tumors as model systems for targeting HIF-2 and the pseudohypoxic phenotype Summary and future perspectives Acknowledgments References ACCEPTED MANUSCRIPT PT Introduction An adequate oxygen supply to cells and tissues is crucial for the function and survival of RI aerobic organisms Hypoxia occurs when oxygen supply fails to meet demand The definition SC of hypoxia is somewhat ambiguous since normal oxygen pressure (PO2) varies between different tissues For instance, the normal PO2 in arterial blood is approximately 100 mmHg (~ NU 13%) but around 40 mmHg (~5%) in the liver (Koh & Powis, 2012) No clear-cut threshold separates normoxia from hypoxia, so oxygen levels must be regarded in context Likewise, MA definitions of mild, moderate, and severe hypoxia are not clearly defined Nevertheless, 8-10 mmHg (~1%) is estimated to represent a critical PO2 since lower PO2 values are associated D with adverse effects caused by reduced O2 consumption (Hockel & Vaupel, 2001) For in TE vitro studies, 1% oxygen is commonly used to mimic a hypoxic environment Solid malignant AC CE P tumors commonly contain hypoxic areas, and direct measurement of tissue oxygenation using O2-sensitive microsensors has shown that the tumor microenvironment is characterized by much lower PO2 values than their normal counterparts (Vaupel, Mayer, & Hockel, 2004) A major cause of tumor hypoxia is the formation of non-functional blood vessels in neoplastic tissue, particularly in rapidly growing tumors Hypoxia is not merely epiphenomenal but is of clinical importance since tumor hypoxia is associated with aggressive tumor phenotypes, treatment resistance, and poor clinical prognosis (reviewed in Bertout et al (Bertout, Patel, & Simon, 2008)) The cellular response to hypoxia is mainly mediated by the hypoxia-inducible factor (HIF) family of transcription factors, which regulate the expression of multiple genes involved in processes that drive the adaptation and progression of cancer cells Therefore, tumor hypoxia and HIFs affect most of the cancer “hallmarks” including cell proliferation, apoptosis, metabolism, immune responses, genomic instability, vascularization, and invasion C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT and metastasis HIFs also appear to contribute to chemo- and radiotherapy resistance via multiple mechanisms In clinical tumor samples, HIF expression is associated with poor PT prognoses and relapse on treatment HIFs appear to be crucial molecular targets that can be exploited to improve on the current treatment of metastatic and treatment-resistant cancer RI However, HIF biology is complex Alternative HIF isoforms differentially regulate tumor SC growth; consequently, optimal HIF targeting depends on the specific tumor type and HIF-1 NU and HIF-2 selectivity Strategies to inhibit HIFs in cancer include drugs with indirect effects on HIF signaling, but direct HIF inhibitors also exist In this review we describe HIF MA regulation and function, their role as master regulators of solid tumor hallmarks (Figure 1), the pseudohypoxic phenotype, and the different therapeutic strategies that have been TE D developed to inhibit HIF activity (Figure 2) AC CE P HIF regulation and function HIFs are proteins that sense and respond to oxygen deficiency by acting as transcription factors (Figure 2) Each HIF transcription factor is composed of two subunits: the α-subunit and the β-subunit, both of which belong to the basic helix-loop-helix (HLH)-PER-ARNT-SIM (bHLH-PAS) protein family (Bersten, Sullivan, Peet, & Whitelaw, 2013) α-subunit stability is oxygen sensitive, while the β-subunit (HIF-1β or ARNT) is ubiquitously expressed In the presence of oxygen, conserved proline residues on the α-subunit are hydroxylated, promoting its degradation (Ivan, et al., 2001; Jaakkola, et al., 2001) This hydroxylation is mediated by prolyl-4-hydroxylases (PHDs), a set of oxygen-, iron-, and ascorbate-dependent enzymes belonging to the 2-oxoglutarate-dependent oxygenase superfamily (Schofield & Ratcliffe, 2004) α-subunit hydroxylation serves as a recognition signal for the von Hippel-Lindau (pVHL) tumor suppressor protein, which subsequently targets the α-subunit for degradation Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT by adding ubiquitin However, under hypoxic conditions, PHDs cannot hydroxylate the αsubunit This results in HIF-α protein stabilization, nuclear translocation, and dimerization to PT HIF-1β to form the HIF transcription factor In the nucleus, HIFs bind to the A/GCGTG consensus motif in target gene promoter regions, known as hypoxia-responsive elements RI (HREs) By recruiting transcriptional co-activators, HIFs regulate the expression of numerous SC genes involved in different processes including angiogenesis, metabolism, erythropoiesis, apoptosis, pH regulation, metastasis, and cellular differentiation (Keith, Johnson, & Simon, NU 2012; Semenza, 2003) MA There are three different α-subunit isoforms: HIF-1α, HIF-2α, and HIF-3α HIF-1α and HIF2α have been most comprehensively studied, with less known about HIF-3α Semenza and D colleagues first described HIF-1α in the nineties (G L Wang, Jiang, Rue, & Semenza, 1995), TE while Tian et al (Tian, McKnight, & Russell, 1997) described the second isoform (initially called EPAS1; endothelial PAS protein 1) soon after, findings that were quickly confirmed by AC CE P several other groups The α-subunits show conserved sequence homology (Figure 3), mostly in the bHLH- and PAS-A and PAS-B domain-containing N-terminal region that mediates DNA binding and interaction with HIF-1β Two transactivation domains (TADs) located in the α-subunit N- and C-termini regulate HIF transcriptional activity: the N-TAD is located in the region where hydroxylation takes place, known as the oxygen-dependent degradation (ODD) domain HIF transcriptional activity is also regulated by a second oxygen-sensitive hydroxylation event mediated by factor inhibiting HIF-1 (FIH-1) (Lando, et al., 2002; Mahon, Hirota, & Semenza, 2001) FIH-1 is a 2-oxoglutarate-dependent oxygenase (similar to the PHDs), and it catalyzes hydroxylation of an asparagine residue in the C-TAD of HIF-α, thereby preventing interaction with the p300/CBP co-activator Of note, HIF-1α is more sensitive to FIH-1-mediated inhibition than HIF-2α (Khan, et al., 2011) due to a specific amino acid difference between the two HIFs (Bracken, et al., 2006) The affinity of PHDs and Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT FIH-1 for oxygen differs and, since FIH-1 has a higher affinity (lower Km) for oxygen, PHDs are thought to be more rapidly inhibited in low oxygen conditions (Pouyssegur, Dayan, & PT Mazure, 2006) Thus, when PHDs are inactive, the HIF-1α subunit is stabilized but FIH-1 can still inhibit transcription of genes that require HIF-1α C-TAD activity Depending on the RI oxygen tension, different gene sets might be regulated according to their N-TAD or C-TAD SC requirement Hypoxia-associated factor (HAF) is an E3 ubiquitin ligase that switches cells from HIF-1- to HIF-2-dependent signaling by targeting HIF-1α for degradation and increasing NU HIF-2α transactivation (Koh, Lemos, Liu, & Powis, 2011) MA The fact that there is less sequence homology in the HIF-1α and HIF-2α transactivating domains than the DNA-binding and heterodimerization domains suggests that HIF-1 and HIF- D have unique target genes Early studies showed that HIF-1 (but not HIF-2) induced TE expression of several glycolytic genes in various cell types, while unique HIF-2 target genes seemed to be cell type specific (C J Hu, Wang, Chodosh, Keith, & Simon, 2003; Raval, et AC CE P al., 2005) The studies were mainly performed in VHL-defective renal cell carcinoma (RCC) cell lines with unique HIF expression patterns, i.e., expressing only HIF-2α or both HIF-1α and HIF-2α HIF transcriptional target specificity was strikingly different in VHL-defective RCC cells compared to other cell types, and the HIF isoforms also showed a mutually dependent suppressive function in RCC (Raval, et al., 2005) Several investigators have used chromatin immunoprecipitation together with microarrays (ChIP-chip) to directly identify HIF target genes (Mole, et al., 2009; Xia & Kung, 2009; Xia, et al., 2009) These studies confirmed the core A/GCGTG HIF-binding motif and, in agreement with earlier findings, showed that HIF-1 targets genes important in glycolytic metabolism Furthermore, genes encoding histone demethylases were identified as HIF-1 target genes, suggesting that HIFs participate in epigenetic homeostasis during hypoxia These studies also identified considerable overlap between HIF-1 and HIF-2 binding sites, yet HIF-2 seemed to contribute Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT very little to the transcriptional changes during hypoxia (Mole, et al., 2009) Integrating data from ChIP-chip analyses with gene expression profiles over a hypoxia time course showed PT that HIF-1 stabilization causes HIF-1 to preferentially bind to loci already transcriptionally active prior to the onset of hypoxia, partially explaining why most hypoxia-induced RI transcriptional changes are cell type specific (Xia & Kung, 2009) A study using chromatin SC immunoprecipitation followed by next-generation high-throughput sequencing (ChIP-seq) showed that HIF binding sites exist outside of promoter sequences and that HIF binds to other NU sites as well as the core A/GCGTG motif (Schodel, et al., 2011) This was particularly true for MA HIF-2α, for which as many as 70% of the identified HIF-2 binding sites lay outside promoter regions Consistent with other studies, glucose metabolism pathways were targeted by HIF-1, while HIF-2 targeted genes were involved in Oct4-regulated stem cell pluripotency A TE D representative list of shared and unique target genes regulated by HIF-1 and HIF-2 can be found in Keith et al (Keith, et al., 2012) Moreover, while HIF-1 is thought to mediate the AC CE P acute response to hypoxia, HIF-2 stabilizes over longer time frames and also at normal physiological oxygen levels (Holmquist-Mengelbier, et al., 2006) In addition to its role as a transcription factor subunit, HIF-2α is also part of a hypoxiaregulated translation initiation complex Hypoxia induces the formation of a HIF-2α complex with the RNA-binding protein RBM4 and cap-binding protein eIF4E2, which is then recruited to a wide variety of mRNAs to promote active translation at polysomes (Uniacke, et al., 2012) This function is independent of HIF-1β dimerization As well as direct gene targeting via HRE binding, both HIF-1α and HIF-2α can indirectly influence gene expression by interfering with the activity of other transcription factors such as MYC (Gordan, Bertout, Hu, Diehl, & Simon, 2007; Koshiji, et al., 2004), p53 (Bertout, et al., 2009; Chen, Li, Luo, & Gu, 2003), and Notch (Gustafsson, et al., 2005; Y Y Hu, et al., 2014) Importantly, for many of these interactions, HIF-1α and HIF-2α seem to have Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT AC CE P TE D MA NU SC RI PT Moeller, B J., Cao, Y., Li, C Y., & Dewhirst, M W (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules Cancer Cell, 5, 429-441 Moeller, B J., Dreher, M R., Rabbani, Z N., Schroeder, T., Cao, Y., Li, C Y., & Dewhirst, M W (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity Cancer Cell, 8, 99-110 Mohlin, S., Hamidian, A., & Pahlman, S (2013) HIF2A and IGF2 expression correlates in human neuroblastoma cells and normal immature sympathetic neuroblasts Neoplasia, 15, 328-334 Mohlin, S., Hamidian, A., von Stedingk, K., Bridges, E., Wigerup, C., Bexell, D., & Pahlman, S (2015) PI3K-mTORC2 but not PI3K-mTORC1 Regulates Transcription of HIF2A/EPAS1 and Vascularization in Neuroblastoma Cancer Res, 75, 4617-4628 Mole, D R., Blancher, C., Copley, R R., Pollard, P J., Gleadle, J M., Ragoussis, J., & Ratcliffe, P J (2009) Genome-wide association of hypoxia-inducible factor (HIF)1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts J Biol Chem, 284, 16767-16775 Molenaar, J J., Domingo-Fernandez, R., Ebus, M E., Lindner, S., Koster, J., Drabek, K., Mestdagh, P., van Sluis, P., Valentijn, L J., van Nes, J., Broekmans, M., Haneveld, F., Volckmann, R., Bray, I., Heukamp, L., Sprussel, A., Thor, T., Kieckbusch, K., KleinHitpass, L., Fischer, M., Vandesompele, J., Schramm, A., van Noesel, M M., Varesio, L., Speleman, F., Eggert, A., Stallings, R L., Caron, H N., Versteeg, R., & Schulte, J H (2012) LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression Nat Genet, 44, 1199-1206 Moreno-Manzano, V., Rodriguez-Jimenez, F J., Acena-Bonilla, J L., Fustero-Lardies, S., Erceg, S., Dopazo, J., Montaner, D., Stojkovic, M., & Sanchez-Puelles, J M (2010) FM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status J Biol Chem, 285, 1333-1342 Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S N., Barrera, J L., Mohar, A., Verastegui, E., & Zlotnik, A (2001) Involvement of chemokine receptors in breast cancer metastasis Nature, 410, 50-56 Munoz-Najar, U M., Neurath, K M., Vumbaca, F., & Claffey, K P (2006) Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation Oncogene, 25, 2379-2392 Nardinocchi, L., Puca, R., Sacchi, A., & D'Orazi, G (2009) Inhibition of HIF-1alpha activity by homeodomain-interacting protein kinase-2 correlates with sensitization of chemoresistant cells to undergo apoptosis Mol Cancer, 8, Nilsson, H., Jogi, A., Beckman, S., Harris, A L., Poellinger, L., & Pahlman, S (2005) HIF2alpha expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia Exp Cell Res, 303, 447456 Noguera, R., Fredlund, E., Piqueras, M., Pietras, A., Beckman, S., Navarro, S., & Pahlman, S (2009) HIF-1alpha and HIF-2alpha are differentially regulated in vivo in neuroblastoma: high HIF-1alpha correlates negatively to advanced clinical stage and tumor vascularization Clin Cancer Res, 15, 7130-7136 Noman, M Z., Desantis, G., Janji, B., Hasmim, M., Karray, S., Dessen, P., Bronte, V., & Chouaib, S (2014) PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation J Exp Med, 211, 781-790 54 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT AC CE P TE D MA NU SC RI PT Nordsmark, M., Alsner, J., Keller, J., Nielsen, O S., Jensen, O M., Horsman, M R., & Overgaard, J (2001) Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations Br J Cancer, 84, 1070-1075 Nordsmark, M., Bentzen, S M., Rudat, V., Brizel, D., Lartigau, E., Stadler, P., Becker, A., Adam, M., Molls, M., Dunst, J., Terris, D J., & Overgaard, J (2005) Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy An international multi-center study Radiother Oncol, 77, 18-24 Nordsmark, M., Loncaster, J., Aquino-Parsons, C., Chou, S C., Gebski, V., West, C., Lindegaard, J C., Havsteen, H., Davidson, S E., Hunter, R., Raleigh, J A., & Overgaard, J (2006) The prognostic value of pimonidazole and tumour pO2 in human cervix carcinomas after radiation therapy: a prospective international multi-center study Radiother Oncol, 80, 123-131 Norris, R E., Shusterman, S., Gore, L., Muscal, J A., Macy, M E., Fox, E., Berkowitz, N., Buchbinder, A., & Bagatell, R (2014) Phase evaluation of EZN-2208, a polyethylene glycol conjugate of SN38, in children adolescents and young adults with relapsed or refractory solid tumors Pediatr Blood Cancer, 61, 1792-1797 Olenyuk, B Z., Zhang, G J., Klco, J M., Nickols, N G., Kaelin, W G., Jr., & Dervan, P B (2004) Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist Proc Natl Acad Sci U S A, 101, 16768-16773 Onnis, B., Rapisarda, A., & Melillo, G (2009) Development of HIF-1 inhibitors for cancer therapy J Cell Mol Med, 13, 2780-2786 Palazon, A., Aragones, J., Morales-Kastresana, A., de Landazuri, M O., & Melero, I (2012) Molecular pathways: hypoxia response in immune cells fighting or promoting cancer Clin Cancer Res, 18, 1207-1213 Pastorino, F., Loi, M., Sapra, P., Becherini, P., Cilli, M., Emionite, L., Ribatti, D., Greenberger, L M., Horak, I D., & Ponzoni, M (2010) Tumor regression and curability of preclinical neuroblastoma models by PEGylated SN38 (EZN-2208), a novel topoisomerase I inhibitor Clin Cancer Res, 16, 4809-4821 Pellegata, N S., Quintanilla-Martinez, L., Siggelkow, H., Samson, E., Bink, K., Hofler, H., Fend, F., Graw, J., & Atkinson, M J (2006) Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans Proc Natl Acad Sci U S A, 103, 15558-15563 Peng, J., Zhang, L., Drysdale, L., & Fong, G H (2000) The transcription factor EPAS1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling Proc Natl Acad Sci U S A, 97, 8386-8391 Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S., & Comoglio, P M (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene Cancer Cell, 3, 347-361 Phillips, R M (2016) Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs Cancer Chemother Pharmacol, 77, 441-457 Phillips, R M., Hendriks, H R., Peters, G J., Pharmacology, E., & Molecular Mechanism, G (2013) EO9 (Apaziquone): from the clinic to the laboratory and back again Br J Pharmacol, 168, 11-18 Pietras, A., Gisselsson, D., Ora, I., Noguera, R., Beckman, S., Navarro, S., & Pahlman, S (2008) High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche J Pathol, 214, 482-488 Pietras, A., Hansford, L M., Johnsson, A S., Bridges, E., Sjolund, J., Gisselsson, D., Rehn, M., Beckman, S., Noguera, R., Navarro, S., Cammenga, J., Fredlund, E., Kaplan, D R., & Pahlman, S (2009) HIF-2alpha maintains an undifferentiated state in neural 55 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT AC CE P TE D MA NU SC RI PT crest-like human neuroblastoma tumor-initiating cells Proc Natl Acad Sci U S A, 106, 16805-16810 Pietras, A., Johnsson, A S., & Pahlman, S (2010) The HIF-2alpha-driven pseudo-hypoxic phenotype in tumor aggressiveness, differentiation, and vascularization Curr Top Microbiol Immunol, 345, 1-20 Piruat, J I., Pintado, C O., Ortega-Saenz, P., Roche, M., & Lopez-Barneo, J (2004) The mitochondrial SDHD gene is required for early embryogenesis, and its partial deficiency results in persistent carotid body glomus cell activation with full responsiveness to hypoxia Mol Cell Biol, 24, 10933-10940 Pouyssegur, J., Dayan, F., & Mazure, N M (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression Nature, 441, 437-443 Powers, J F., Evinger, M J., Tsokas, P., Bedri, S., Alroy, J., Shahsavari, M., & Tischler, A S (2000) Pheochromocytoma cell lines from heterozygous neurofibromatosis knockout mice Cell Tissue Res, 302, 309-320 Qin, N., de Cubas, A A., Garcia-Martin, R., Richter, S., Peitzsch, M., Menschikowski, M., Lenders, J W., Timmers, H J., Mannelli, M., Opocher, G., Economopoulou, M., Siegert, G., Chavakis, T., Pacak, K., Robledo, M., & Eisenhofer, G (2014) Opposing effects of HIF1alpha and HIF2alpha on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC-associated factor X Int J Cancer, 135, 20542064 Ramanathan, R K., Abbruzzese, J., Dragovich, T., Kirkpatrick, L., Guillen, J M., Baker, A F., Pestano, L A., Green, S., & Von Hoff, D D (2011) A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination Cancer Chemother Pharmacol, 67, 503-509 Rankin, E B., Biju, M P., Liu, Q., Unger, T L., Rha, J., Johnson, R S., Simon, M C., Keith, B., & Haase, V H (2007) Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo J Clin Invest, 117, 1068-1077 Rapisarda, A., Uranchimeg, B., Scudiero, D A., Selby, M., Sausville, E A., Shoemaker, R H., & Melillo, G (2002) Identification of small molecule inhibitors of hypoxiainducible factor transcriptional activation pathway Cancer Res, 62, 4316-4324 Rapisarda, A., Zalek, J., Hollingshead, M., Braunschweig, T., Uranchimeg, B., Bonomi, C A., Borgel, S D., Carter, J P., Hewitt, S M., Shoemaker, R H., & Melillo, G (2004) Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts Cancer Res, 64, 6845-6848 Raskatov, J A., Szablowski, J O., & Dervan, P B (2014) Tumor xenograft uptake of a pyrrole-imidazole (Py-Im) polyamide varies as a function of cell line grafted J Med Chem, 57, 8471-8476 Raval, R R., Lau, K W., Tran, M G., Sowter, H M., Mandriota, S J., Li, J L., Pugh, C W., Maxwell, P H., Harris, A L., & Ratcliffe, P J (2005) Contrasting properties of hypoxia-inducible factor (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma Mol Cell Biol, 25, 5675-5686 Ravi, R., Mookerjee, B., Bhujwalla, Z M., Sutter, C H., Artemov, D., Zeng, Q., Dillehay, L E., Madan, A., Semenza, G L., & Bedi, A (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha Genes Dev, 14, 34-44 Reece, K M., Richardson, E D., Cook, K M., Campbell, T J., Pisle, S T., Holly, A J., Venzon, D J., Liewehr, D J., Chau, C H., Price, D K., & Figg, W D (2014) Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo 56 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT AC CE P TE D MA NU SC RI PT antitumor activity by disrupting the HIF-1alpha/p300 complex in a preclinical model of prostate cancer Mol Cancer, 13, 91 Reynolds, T Y., Rockwell, S., & Glazer, P M (1996) Genetic instability induced by the tumor microenvironment Cancer Res, 56, 5754-5757 Richter, S., Qin, N., Pacak, K., & Eisenhofer, G (2013) Role of hypoxia and HIF2alpha in development of the sympathoadrenal cell lineage and chromaffin cell tumors with distinct catecholamine phenotypic features Adv Pharmacol, 68, 285-317 Rischin, D., Peters, L J., O'Sullivan, B., Giralt, J., Fisher, R., Yuen, K., Trotti, A., Bernier, J., Bourhis, J., Ringash, J., Henke, M., & Kenny, L (2010) Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group J Clin Oncol, 28, 2989-2995 Roberts, A M., Watson, I R., Evans, A J., Foster, D A., Irwin, M S., & Ohh, M (2009) Suppression of hypoxia-inducible factor 2alpha restores p53 activity via Hdm2 and reverses chemoresistance of renal carcinoma cells Cancer Res, 69, 9056-9064 Rohwer, N., & Cramer, T (2011) Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways Drug Resist Updat, 14, 191201 Roizin-Towle, L., & Hall, E J (1978) Studies with bleomycin and misonidazole on aerated and hypoxic cells Br J Cancer, 37, 254-260 Rundqvist, H., & Johnson, R S (2010) Hypoxia and metastasis in breast cancer Curr Top Microbiol Immunol, 345, 121-139 Ryan, H E., Lo, J., & Johnson, R S (1998) HIF-1 alpha is required for solid tumor formation and embryonic vascularization EMBO J, 17, 3005-3015 Sanchez, M., Galy, B., Muckenthaler, M U., & Hentze, M W (2007) Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency Nat Struct Mol Biol, 14, 420-426 Scheuermann, T H., Li, Q., Ma, H W., Key, J., Zhang, L., Chen, R., Garcia, J A., Naidoo, J., Longgood, J., Frantz, D E., Tambar, U K., Gardner, K H., & Bruick, R K (2013) Allosteric inhibition of hypoxia inducible factor-2 with small molecules Nat Chem Biol, 9, 271-276 Scheuermann, T H., Tomchick, D R., Machius, M., Guo, Y., Bruick, R K., & Gardner, K H (2009) Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor Proc Natl Acad Sci U S A, 106, 450-455 Schindl, M., Schoppmann, S F., Samonigg, H., Hausmaninger, H., Kwasny, W., Gnant, M., Jakesz, R., Kubista, E., Birner, P., Oberhuber, G., Austrian, B., & Colorectal Cancer Study, G (2002) Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer Clin Cancer Res, 8, 1831-1837 Schnell, P O., Ignacak, M L., Bauer, A L., Striet, J B., Paulding, W R., & Czyzyk-Krzeska, M F (2003) Regulation of tyrosine hydroxylase promoter activity by the von HippelLindau tumor suppressor protein and hypoxia-inducible transcription factors J Neurochem, 85, 483-491 Schodel, J., Oikonomopoulos, S., Ragoussis, J., Pugh, C W., Ratcliffe, P J., & Mole, D R (2011) High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq Blood, 117, e207-217 Schofield, C J., & Ratcliffe, P J (2004) Oxygen sensing by HIF hydroxylases Nat Rev Mol Cell Biol, 5, 343-354 Schoppmann, S F., Fenzl, A., Schindl, M., Bachleitner-Hofmann, T., Nagy, K., Gnant, M., Horvat, R., Jakesz, R., & Birner, P (2006) Hypoxia inducible factor-1alpha correlates 57 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT AC CE P TE D MA NU SC RI PT with VEGF-C expression and lymphangiogenesis in breast cancer Breast Cancer Res Treat, 99, 135-141 Schulz, N., Propst, F., Rosenberg, M P., Linnoila, R I., Paules, R S., Kovatch, R., Ogiso, Y., & Vande Woude, G (1992) Pheochromocytomas and C-cell thyroid neoplasms in transgenic c-mos mice: a model for the human multiple endocrine neoplasia type syndrome Cancer Res, 52, 450-455 Scortegagna, M., Ding, K., Oktay, Y., Gaur, A., Thurmond, F., Yan, L J., Marck, B T., Matsumoto, A M., Shelton, J M., Richardson, J A., Bennett, M J., & Garcia, J A (2003) Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice Nat Genet, 35, 331-340 Semenza, G L (2003) Targeting HIF-1 for cancer therapy Nat Rev Cancer, 3, 721-732 Semenza, G L (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy Trends Pharmacol Sci, 33, 207-214 Semenza, G L (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations J Clin Invest, 123, 3664-3671 Shin, D H., Chun, Y S., Lee, D S., Huang, L E., & Park, J W (2008) Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxiainducible factor-1 Blood, 111, 3131-3136 Shin, D H., Kim, J H., Jung, Y J., Kim, K E., Jeong, J M., Chun, Y S., & Park, J W (2007) Preclinical evaluation of YC-1, a HIF inhibitor, for the prevention of tumor spreading Cancer Lett, 255, 107-116 Shultz, L D., Goodwin, N., Ishikawa, F., Hosur, V., Lyons, B L., & Greiner, D L (2014) Human cancer growth and therapy in immunodeficient mouse models Cold Spring Harb Protoc, 2014, 694-708 Shweiki, D., Itin, A., Soffer, D., & Keshet, E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis Nature, 359, 843845 Simiantonaki, N., Taxeidis, M., Jayasinghe, C., Kurzik-Dumke, U., & Kirkpatrick, C J (2008) Hypoxia-inducible factor alpha expression increases during colorectal carcinogenesis and tumor progression BMC Cancer, 8, 320 Singleton, D C., Rouhi, P., Zois, C E., Haider, S., Li, J L., Kessler, B M., Cao, Y., & Harris, A L (2015) Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis Oncogene, 34, 4713-4722 Sivridis, E., Giatromanolaki, A., Gatter, K C., Harris, A L., Koukourakis, M I., Tumor, & Angiogenesis Research, G (2002) Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma Cancer, 95, 1055-1063 Smith-Hicks, C L., Sizer, K C., Powers, J F., Tischler, A S., & Costantini, F (2000) C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B EMBO J, 19, 612-622 Staller, P., Sulitkova, J., Lisztwan, J., Moch, H., Oakeley, E J., & Krek, W (2003) Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL Nature, 425, 307-311 Sullivan, R., & Graham, C H (2009) Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor Mol Cancer Ther, 8, 1702-1713 Taieb, D., Yang, C., Delenne, B., Zhuang, Z., Barlier, A., Sebag, F., & Pacak, K (2013) First report of bilateral pheochromocytoma in the clinical spectrum of HIF2A-related polycythemia-paraganglioma syndrome J Clin Endocrinol Metab, 98, E908-913 58 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT AC CE P TE D MA NU SC RI PT Tannock, I F (1968) The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour Br J Cancer, 22, 258-273 Teitz, T., Inoue, M., Valentine, M B., Zhu, K., Rehg, J E., Zhao, W., Finkelstein, D., Wang, Y D., Johnson, M D., Calabrese, C., Rubinstein, M., Hakem, R., Weiss, W A., & Lahti, J M (2013) Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis Cancer Res, 73, 4086-4097 Terzuoli, E., Puppo, M., Rapisarda, A., Uranchimeg, B., Cao, L., Burger, A M., Ziche, M., & Melillo, G (2010) Aminoflavone, a ligand of the aryl hydrocarbon receptor, inhibits HIF-1alpha expression in an AhR-independent fashion Cancer Res, 70, 6837-6848 Thomas, G V., Tran, C., Mellinghoff, I K., Welsbie, D S., Chan, E., Fueger, B., Czernin, J., & Sawyers, C L (2006) Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer Nat Med, 12, 122-127 Tian, H., Hammer, R E., Matsumoto, A M., Russell, D W., & McKnight, S L (1998) The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development Genes Dev, 12, 3320-3324 Tian, H., McKnight, S L., & Russell, D W (1997) Endothelial PAS domain protein (EPAS1), a transcription factor selectively expressed in endothelial cells Genes Dev, 11, 72-82 To, K K., Sedelnikova, O A., Samons, M., Bonner, W M., & Huang, L E (2006) The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repression EMBO J, 25, 4784-4794 Toledo, R A., Qin, Y., Srikantan, S., Morales, N P., Li, Q., Deng, Y., Kim, S W., Pereira, M A., Toledo, S P., Su, X., Aguiar, R C., & Dahia, P L (2013) In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas Endocr Relat Cancer, 20, 349-359 Uniacke, J., Holterman, C E., Lachance, G., Franovic, A., Jacob, M D., Fabian, M R., Payette, J., Holcik, M., Pause, A., & Lee, S (2012) An oxygen-regulated switch in the protein synthesis machinery Nature, 486, 126-129 Unruh, A., Ressel, A., Mohamed, H G., Johnson, R S., Nadrowitz, R., Richter, E., Katschinski, D M., & Wenger, R H (2003) The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy Oncogene, 22, 3213-3220 Vander Heiden, M G., Cantley, L C., & Thompson, C B (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation Science, 324, 10291033 Wang, G L., Jiang, B H., Rue, E A., & Semenza, G L (1995) Hypoxia-inducible factor is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension Proc Natl Acad Sci U S A, 92, 5510-5514 Wang, Y., Liu, Y., Tang, F., Bernot, K M., Schore, R., Marcucci, G., Caligiuri, M A., Zheng, P., & Liu, Y (2014) Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells Blood, 124, 1127-1135 Vaupel, P., & Mayer, A (2007) Hypoxia in cancer: significance and impact on clinical outcome Cancer Metastasis Rev, 26, 225-239 Vaupel, P., Mayer, A., & Hockel, M (2004) Tumor hypoxia and malignant progression Methods Enzymol, 381, 335-354 Weiss, W A., Aldape, K., Mohapatra, G., Feuerstein, B G., & Bishop, J M (1997) Targeted expression of MYCN causes neuroblastoma in transgenic mice EMBO J, 16, 29852995 59 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT AC CE P TE D MA NU SC RI PT Welsh, S., Williams, R., Kirkpatrick, L., Paine-Murrieta, G., & Powis, G (2004) Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha Mol Cancer Ther, 3, 233-244 Welsh, S J., Bellamy, W T., Briehl, M M., & Powis, G (2002) The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis Cancer Res, 62, 5089-5095 Welsh, S J., Williams, R R., Birmingham, A., Newman, D J., Kirkpatrick, D L., & Powis, G (2003) The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation Mol Cancer Ther, 2, 235-243 Vergis, R., Corbishley, C M., Norman, A R., Bartlett, J., Jhavar, S., Borre, M., Heeboll, S., Horwich, A., Huddart, R., Khoo, V., Eeles, R., Cooper, C., Sydes, M., Dearnaley, D., & Parker, C (2008) Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study Lancet Oncol, 9, 342-351 White, E (2012) Deconvoluting the context-dependent role for autophagy in cancer Nat Rev Cancer, 12, 401-410 Wilson, W R., & Hay, M P (2011) Targeting hypoxia in cancer therapy Nat Rev Cancer, 11, 393-410 Volm, M., & Koomagi, R (2000) Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer Anticancer Res, 20, 1527-1533 Xia, X., & Kung, A L (2009) Preferential binding of HIF-1 to transcriptionally active loci determines cell-type specific response to hypoxia Genome Biol, 10, R113 Xia, X., Lemieux, M E., Li, W., Carroll, J S., Brown, M., Liu, X S., & Kung, A L (2009) Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis Proc Natl Acad Sci U S A, 106, 4260-4265 Yang, C., Sun, M G., Matro, J., Huynh, T T., Rahimpour, S., Prchal, J T., Lechan, R., Lonser, R., Pacak, K., & Zhuang, Z (2013) Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas Blood, 121, 2563-2566 Yang, M H., Wu, M Z., Chiou, S H., Chen, P M., Chang, S Y., Liu, C J., Teng, S C., & Wu, K J (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis Nat Cell Biol, 10, 295-305 Yeo, E J., Chun, Y S., Cho, Y S., Kim, J., Lee, J C., Kim, M S., & Park, J W (2003) YC1: a potential anticancer drug targeting hypoxia-inducible factor J Natl Cancer Inst, 95, 516-525 Yeo, E J., Ryu, J H., Cho, Y S., Chun, Y S., Huang, L E., Kim, M S., & Park, J W (2006) Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIHmediated repression of HIF-1 Blood, 107, 916-923 You, M J., Castrillon, D H., Bastian, B C., O'Hagan, R C., Bosenberg, M W., Parsons, R., Chin, L., & DePinho, R A (2002) Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice Proc Natl Acad Sci U S A, 99, 1455-1460 Young, S D., Marshall, R S., & Hill, R P (1988) Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells Proc Natl Acad Sci U S A, 85, 9533-9537 60 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT AC CE P TE D MA NU SC RI PT Yuan, J., Narayanan, L., Rockwell, S., & Glazer, P M (2000) Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH Cancer Res, 60, 4372-4376 Yuneva, M., Zamboni, N., Oefner, P., Sachidanandam, R., & Lazebnik, Y (2007) Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells J Cell Biol, 178, 93-105 Zhang, H., Bosch-Marce, M., Shimoda, L A., Tan, Y S., Baek, J H., Wesley, J B., Gonzalez, F J., & Semenza, G L (2008) Mitochondrial autophagy is an HIF-1dependent adaptive metabolic response to hypoxia J Biol Chem, 283, 10892-10903 Zhang, H., Gao, P., Fukuda, R., Kumar, G., Krishnamachary, B., Zeller, K I., Dang, C V., & Semenza, G L (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity Cancer Cell, 11, 407-420 Zhang, H., Qian, D Z., Tan, Y S., Lee, K., Gao, P., Ren, Y R., Rey, S., Hammers, H., Chang, D., Pili, R., Dang, C V., Liu, J O., & Semenza, G L (2008) Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth Proc Natl Acad Sci U S A, 105, 19579-19586 Zhang, H., Wong, C C., Wei, H., Gilkes, D M., Korangath, P., Chaturvedi, P., Schito, L., Chen, J., Krishnamachary, B., Winnard, P T., Jr., Raman, V., Zhen, L., Mitzner, W A., Sukumar, S., & Semenza, G L (2012) HIF-1-dependent expression of angiopoietin-like and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs Oncogene, 31, 1757-1770 Zhang, X., Kon, T., Wang, H., Li, F., Huang, Q., Rabbani, Z N., Kirkpatrick, J P., Vujaskovic, Z., Dewhirst, M W., & Li, C Y (2004) Enhancement of hypoxiainduced tumor cell death in vitro and radiation therapy in vivo by use of small interfering RNA targeted to hypoxia-inducible factor-1alpha Cancer Res, 64, 81398142 Zhao, D., Zhai, B., He, C., Tan, G., Jiang, X., Pan, S., Dong, X., Wei, Z., Ma, L., Qiao, H., Jiang, H., & Sun, X (2014) Upregulation of HIF-2alpha induced by sorafenib contributes to the resistance by activating the TGF-alpha/EGFR pathway in hepatocellular carcinoma cells Cell Signal, 26, 1030-1039 Zhong, H., Agani, F., Baccala, A A., Laughner, E., Rioseco-Camacho, N., Isaacs, W B., Simons, J W., & Semenza, G L (1998) Increased expression of hypoxia inducible factor-1alpha in rat and human prostate cancer Cancer Res, 58, 5280-5284 Zhong, H., Chiles, K., Feldser, D., Laughner, E., Hanrahan, C., Georgescu, M M., Simons, J W., & Semenza, G L (2000) Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics Cancer Res, 60, 1541-1545 Zhong, H., De Marzo, A M., Laughner, E., Lim, M., Hilton, D A., Zagzag, D., Buechler, P., Isaacs, W B., Semenza, G L., & Simons, J W (1999) Overexpression of hypoxiainducible factor 1alpha in common human cancers and their metastases Cancer Res, 59, 5830-5835 Zhou, Q., Gustafson, D., Nallapareddy, S., Diab, S., Leong, S., Lewis, K., Gore, L., Messersmith, W A., Treston, A M., Eckhardt, S G., Sidor, C., & Camidge, D R (2011) A phase I dose-escalation, safety and pharmacokinetic study of the 2methoxyestradiol analog ENMD-1198 administered orally to patients with advanced cancer Invest New Drugs, 29, 340-346 Zhou, Z L., Luo, Z G., Yu, B., Jiang, Y., Chen, Y., Feng, J M., Dai, M., Tong, L J., Li, Z., Li, Y C., Ding, J., & Miao, Z H (2010) Increased accumulation of hypoxia61 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT AC CE P TE D MA NU SC RI PT inducible factor-1alpha with reduced transcriptional activity mediates the antitumor effect of triptolide Mol Cancer, 9, 268 Zhuang, Z., Yang, C., Lorenzo, F., Merino, M., Fojo, T., Kebebew, E., Popovic, V., Stratakis, C A., Prchal, J T., & Pacak, K (2012) Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia N Engl J Med, 367, 922-930 Zimmer, M., Ebert, B L., Neil, C., Brenner, K., Papaioannou, I., Melas, A., Tolliday, N., Lamb, J., Pantopoulos, K., Golub, T., & Iliopoulos, O (2008) Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing Mol Cell, 32, 838-848 62 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an AC CE P TE D MA NU SC RI PT ACCEPTED MANUSCRIPT Figure 63 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an Figure AC CE P TE D MA NU SC RI PT ACCEPTED MANUSCRIPT 64 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an AC CE P TE D MA NU SC RI PT ACCEPTED MANUSCRIPT Figure 65 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an AC CE P TE D MA NU SC RI PT ACCEPTED MANUSCRIPT Figure 66 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT Table Inhibitors of HIF activity by different mechanisms and targets Target References Wortmannin LY94002 GDC-0941 PI-103 Rapamycin PP242 Aminoflavone Glyceollins PI3K PI3K PI3K PI3K mTOR mTOR unknown AKT/mTOR, Hsp90 Topotecan, PEG-SN38 EZN-2968 Topoisomerase HIF-1α mRNA 2ME2, ENMD-1198 Geldanamycin and analogues Vorinostat YC-1 PX-478 PX-12, pleurotin Cardiac glycosides FM19G11 HIF-2α translational inhibitors Microtubules Jiang et al 2001 Jiang et al 2001, Mohlin et al 2015 Mohlin et al 2015 Mohlin et al 2015 Hudson et al 2002 Mohlin et al 2015 Terzuoli et al 2010 Lee et al 2015 Rapisarda et al 2004, Pastorino et al 2010 Greenberger et al 2008 Mabjeesh et al 2003, LaVallee et al 2008 DNA binding Transcriptional activity RI SC NU Isaacs et al 2002 Hutt et al 2014 Chun et al 2001, Li et al 2008 Koh et al 2008 Welsh et al 2003 Zhang et al 2008 Moreno-Manzano et al 2010 IRP1/IRE interaction Zimmer et al 2008 HIF-1α/2α PAS-B domain HIF-2α PAS-B domain Lee et al 2009 Scheuermann et al 2013 Echinomycin Polyamides HRE HRE Kong et al 2005 Olenyuk et al 2004 Chetomin p300 recruitment Bortezomib p300 recruitment FIH-1 interaction and p300 recruitment Hsp70 Thioredoxin-1 Kung et al 2004 Kaluz et al 2006, Shin et al 2008 MA Hsp90 HDAC unknown unknown Thioredoxin-1 unknown unknown TE Acriflavine PT2385 AC CE P HIF-α / HIF-1β dimerization PT Drug D Inhibitory mechanism mRNA/protein expression Amphotericin B Triptolide AJM290, AW464 Yeo et al 2006 Zhou et al 2010 Jones et al 2006 PI3K, phosphoinositide 3-kinase; mTOR, mechanistic/mammalian target of rapamycin; Hsp90, heat shock protein 90; HDAC, histone deacetylase; IRP1, iron-responsive element-binding protein 1; IRE, iron response element; HRE, hypoxia response element; FIH, factor inhibiting HIF; Hsp70, heat shock protein 70 67 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an ACCEPTED MANUSCRIPT Table Examples of hypoxia prodrugs in preclinical and clinical trials Clinical trial status Phase III Phase III (active) Phase III (completed) Cancer Soft tissue sarcoma Pancreatic cancer Bladder cancer PT Prodrug TH-302 (Evofosfamide) EO9 (Apaziquone) SC Multiple NU PR-104 Tirapazamine (TPZ) Phase I/II Phase I /II Phase I Phase I/II (completed) Phase III (completed) Acute leukemia Cervical cancer Head and neck cancer MA AQ4N RI Phase III (active) Preclinical TE Phase II (active) Non small cell lung cancer Squamous cell carcinoma NCT02454842 NCT02449681 AC CE P SN30000 (CEN-209) TH-4000 D Lung cancer NCT NCT01440088 NCT01746979 NCT00598806 NCT00461591 NCT01410565 NCT02563561 NCT01469221 NCT00394628 NCT00109356 NCT00090727 NCT01037556 NCT00262821 NCT00174837 NCT00094081 NCT00017459 NCT00006484 68 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn