Abstract
Cytotoxic anti-cancer agents induce apoptosis in tumor and normal tissues. Therefore, it is important to investigate which factors determine these apoptotic processes and hence their likely impact on therapeutic gain. Radiation-induced apoptosis in tumors may be inhibited due to mutations of apoptotic elements or to tumor microenvironmental conditions arising from vascular insufficiency. Tumors typically contain regions of hypoxia, low glucose and acidosis. Hypoxic cells compromise treatment partly because of reduced fixation of damage during radiotherapy and partly because they promote a more malignant phenotype. There is also evidence that hypoxia may inhibit apoptosis. For some cell types, concurrent hypoxia may modulate radiation-induced apoptosis while, for others, post-irradiation hypoxia may be required. This may reflect the activity of different apoptotic pathways. Pathways involving mitochondrial components as well as regulation of SAPK and Fas have been implicated. In addition, several key stages in apoptosis are sensitive to depletion of cellular energy reserves, which results from hypoxia and low glucose conditions. There is also evidence that low pH in tumors can interfere with radiation-induced apoptosis, partly through cell cycle arrest and other undefined mechanisms. Conclusions: Hypoxia, low glucose and acidosis influence radiation-induced apoptosis and thus may be detrimental to radiotherapy.
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References
Vaupel P (2004) Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 14(3):198–206
Erb P, Ji J, Wernli M, et al (2005) Role of apoptosis in basal cell and squamous cell carcinoma formation. Immunol Lett 100(1):68–72
Vaupel P (1990) Oxygenation of human tumors. Strahlenther Onkol 166(6):377–386
Vaupel P, Schlenger K, Knoop C, et al (1991) Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 51(12):3316–3322
Koong AC, Mehta VK, Le QT, et al (2000) Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 48(4):919–922
Nordsmark M, Overgaard J (2000) A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy. Radiother Oncol 57(1):39–43
Rofstad EK, Sundfor K, Lyng H, et al (2000) Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis. Br J Cancer 83(3):354–359
Harrison LB, Chadha M, Hill RJ, et al (2002) Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist 7(6):492–508
Nordsmark M, Bentzen SM, Rudat V, et al (2005) Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 77(1):18–24
Hockel M, Schlenger K, Aral B, et al (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56(19):4509–4515
Hopcia KL, McCarey YL, Sylvester FC, et al (1996) Radiation-induced apoptosis in HL60 cells: oxygen effect, relationship between apoptosis and loss of clonogenicity, and dependence of time to apoptosis on radiation dose. Radiat Res 145(3):315–323
Klassen NV, Walker PR, Ross CK, et al (1993) Two-stage cell shrinkage and the OER for radiation-induced apoptosis of rat thymocytes. Int J Radiat Biol 64(5):571–581
Horsman MR (1995) Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours. Acta Oncol 34(5):571–587
Vora S, Halper JP, Knowles DM (1985) Alterations in the activity and isozymic profile of human phosphofructokinase during malignant transformation in vivo and in vitro: transformation- and progression-linked discriminants of malignancy. Cancer Res 45(7):2993–3001
Medina RA, Owen GI (2002) Glucose transporters: expression, regulation and cancer. Biol Res 35(1):9–26
Airley R, Loncaster J, Davidson S, et al (2001) Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. Clin Cancer Res 7(4):928–934
Seagroves TN, Ryan HE, Lu H, et al (2001) Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells. Mol Cell Biol 21(10):3436–3444
Vordermark D, Kraft P, Katzer A, et al (2005) Glucose requirement for hypoxic accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha). Cancer Lett 230(1):122–133
Kwon SJ, Lee YJ (2005) Effect of low glutamine/glucose on hypoxia-induced elevation of hypoxia-inducible factor-1alpha in human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells. Clin Cancer Res 11(13):4694–4700
Stubbs M, McSheehy PM, Griffiths JR, et al (2000) Causes and consequences of tumour acidity and implications for treatment. Mol Med Today 6(1):15–19
Amellem O, Pettersen EO (1991) The role of protein accumulation on the kinetics of entry into S phase following extreme hypoxia. Anticancer Res 11(3):1083–1087
Yuan J, Narayanan L, Rockwell S, et al (2000) Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and Low pH. Cancer Res 60(16):4372–4376
Belka C, Jendrossek V, Pruschy M, et al (2004) Apoptosis-modulating agents in combination with radiotherapy-current status and outlook. Int J Radiat Oncol Biol Phys 58(2):542–554
Brizel DM, Dodge RK, Clough RW, et al (1999) Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 53(2):113–117
Enoch T, Norbury C (1995) Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM. Trends Biochem Sci 20(10):426−430
Zgheib O, Huyen Y, DiTullio RA, et al (2005) ATM signaling and 53BP1. Radiother Oncol 76:119–122
Rogoff HA, Pickering MT, Frame FM, et al (2004) Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2. Mol Cell Biol 24(7):2968–2977
Pusapati RV, Rounbehler RJ, Hong S, et al (2006) ATM promotes apoptosis and suppresses tumorigenesis in response to Myc. Proc Natl Acad Sci USA 103(5):1446–1451
Verheij M, Bose R, Lin XH, et al (1996) Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380(6569):75–79
von Haefen C, Wieder T, Gillissen B, et al (2002) Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 21(25):4009–4019
Kolesnick R, Fuks Z (2003) Radiation and ceramide-induced apoptosis. Oncogene 22(37):5897–5906
Kimura K, Gelmann EP (2000) Tumor Necrosis Factor-α and Fas activate complementary Fas-associated Death Domain-dependent pathways that enhance apoptosis induced by γ-Irradiation. J Biol Chem 275(12):8610–8617
Hamasu T, Inanami O, Tsujitani M, et al (2005) Post-irradiation hypoxic incubation of X-irradiated MOLT-4 cells reduces apoptotic cell death by changing the intracellular redox state and modulating SAPK/JNK pathways. Apoptosis 10(3):557–567
Inanami O, Sugihara K, Okui T, et al (2002) Hypoxia and etanidazole alter radiation-induced apoptosis in HL60 cells but not in MOLT-4 cells. Int J Radiat Biol 78(4):267–274
Weinmann M, Marini P, Jendrossek V, et al (2004) Influence of hypoxia on TRAIL-induced apoptosis in tumor cells. Int J Radiat Oncol Biol Phys 58(2):386–396
Samuni AM, Kasid U, Chuang EY, et al (2005) Effects of hypoxia on radiation-responsive stress-activated protein kinase, p53, and caspase 3 signals in TK6 human lymphoblastoid cells. Cancer Res 65(2):579–586
Weinmann M, Jendrossek V, Guner D, et al (2004) Cyclic exposure to hypoxia and reoxygenation selects for tumor cells with defects in mitochondrial apoptotic pathways. FASEB J 18(15):1906–1908
Cuisnier O, Serduc R, Lavieille JP, et al (2003) Chronic hypoxia protects against gamma-irradiation-induced apoptosis by inducing bcl-2 up-regulation and inhibiting mitochondrial translocation and conformational change of bax protein. Int J Oncol 23(4):1033–1041
Graeber TG, Osmanian C, Jacks T, et al (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379(6560):88–91
Vaupel P, Hockel M (2003) Tumor oxygenation and its relevance to tumor physiology and treatment. Adv Exp Med Biol 510:45–49
Soengas MS, Alarcon RM, Yoshida H, et al (1999) Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science 284(5411):156–159
Hammond EM, Giaccia AJ (2005) The role of p53 in hypoxia-induced apoptosis. Biochem Biophys Res Commun 331(3):718–725
Dong Z, Wang J (2004) Hypoxia selection of death-resistant cells. A role for Bcl-X(L). J Biol Chem 279(10):9215–9221
Weinmann M, Belka C, Guner D, et al (2005) Array-based comparative gene expression analysis of tumor cells with increased apoptosis resistance after hypoxic selection. Oncogene 24(38):5914–5922
Koumenis C, Naczki C, Koritzinsky M, et al (2002) Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol 22(21):7405–7416
Graeber TG, Peterson JF, Tsai M, et al (1994) Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol 14(9):6264–6277
Amellem O, Loffler M, Pettersen EO (1994) Regulation of cell proliferation under extreme and moderate hypoxia: the role of pyrimidine (deoxy) nucleotides. Br J Cancer 70(5):857–866
Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93(4):266–276
Shinomiya N, Kuno Y, Yamamoto F, et al (2000) Different mechanisms between premitotic apoptosis and postmitotic apoptosis in X-irradiated U937 cells. Int J Radiat Oncol Biol Phys 47(3):767–777
Ljungkvist AS, Bussink J, Kaanders JH, et al (2006) Dynamics of hypoxia, proliferation and apoptosis after irradiation in a murine tumor model. Radiat Res 165(3):326–336
Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. JNCI 93(4):266–276
Papendreou I, Powell A, Lim AL, et al (2005) Cellular reaction to hypoxia: sensing and responding to an adverse environment. Mutat Res 569(1–2):87–100
Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88(4):1474–1480
Gross J, Fuchs J, Machulik A, et al (2005) Apoptosis, necrosis and hypoxia inducible factor-1 in human head and neck squamous cell carcinoma cultures. Int J Oncol 27(3):807–814
Aebersold DM, Burri P, Beer KT, et al (2001) Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61(7):2911–2916
Moeller BJ, Cao Y, Li CY, et al (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5(5):429–441
Greijer AE, van der Wall E (2004) The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Path 57(10):1009–1014
Piret JP, Mottet D, Raes M, et al (2002) Is HIF-1alpha a pro- or an anti-apoptotic protein? Biochem Pharmacol 64(5–6):889–892
Suzuki H, Tomida A, Tsuruo T (2001) Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene 20(41):5779–5788
Sowter HM, Ratcliffe PJ, Watson P, et al (2001) HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 61(18):6669–6673
Sonveaux P, Dessy C, Brouet A, et al (2002) Modulation of the tumor vasculature functionality by ionizing radiation accounts for tumor radiosensitization and promotes gene delivery. FASEB J 16(14):1979–1981
Gorski DH, Beckett MA, Jaskowiak NT, et al (1999) Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 59(14):3374–3378
Kumar P, Miller AI, Polverini PJ (2004) p38 MAPK mediates gamma-irradiation-induced endothelial cell apoptosis, and vascular endothelial growth factor protects endothelial cells through the phosphoinositide 3-kinase-Akt-Bcl-2 pathway. J Biol Chem 279(41):43352–43360
Moeller BJ, Cao Y, Li CY, et al (2005) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5(5):429–441
Green DR, Reed JC (1998) Mitochondria and apoptosis. Sci 281(5381):1309–1312
Tamatani M, Mitsuda N, Matsuzaki H, et al (2000) A pathway of neuronal apoptosis induced by hypoxia/reoxygenation: roles of nuclear factor-kappaB and Bcl-2. J Neurochem 75(2):683–693
Basu S, Rosenzweig KR, Youmell M, et al (1998) The DNA-dependent protein kinase participates in the activation of NF kappa B following DNA damage. Biochem Biophys Res Commun 247(1):79–83
Luo JL, Kamata H Karin M (2005) IKK/NF-KB signaling: balancing life and death—a new approach to cancer therapy. J Clin Invest 115(10):2625–2632
Halicka HD, Ardelt B, Li X, et al (1995) 2-Deoxy-D-glucose enhances sensitivity of human histiocytic lymphoma U937 cells to apoptosis induced by tumor necrosis factor. Cancer Res 55(2):444–449
Haga N, Naito M, Seimiya H, et al (1998) 2-Deoxyglucose inhibits chemotherapeutic drug-induced apoptosis in human monocytic leukemia U937 cells with inhibition of C-Jun N-terminal kinase 1/stress-activated protein kinase activation. Int J Cancer 76(1):86–90
Wilhelm S, Roloff S, Hacker G (1997) Inhibition of etoposide-induced apoptotic events by azide. Immunol Lett 59(1):53–59
Munoz-Pinedo C, Ruiz-Ruiz C, Ruiz de Almodovar C, et al (2003) Inhibition of glucose metabolism sensitizes tumor cells to death receptor-triggered apoptosis through enhancement of death-inducing signaling complex formation and apical procaspase-8 processing. J Biol Chem 278(15):12759–12768
Liu X, Kim CN, Yang J, et al (1996) Induction of apoptotic program in cell free extracts: requirement for dATP and cytochrome C. Cell 86(1):147–157
Yasuhara N, Eguchi Y, Tachibana T, et al (1997) Essential role of active nuclear transport in apoptosis. Genes to Cells 2(1):55–64
Lee J, Paull TT (2005) ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Sci 308(5721):551–554
Xu RH, Pelicano H, Zhou Y, et al (2005) Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 65(2):613–621
Colussi C, Albertini MC, Coppola S, et al (2000) H202-induced block of glycolysis as an active ADP-ribosylation reaction protecting cells from apoptosis. FASEB J 14(14):2266–2276
Danial NN, Gramm CF, Scooano L, et al (2003) BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424(6951):952–956
Pastorino JG, Shulga N, Hoek JB (2002) Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem 277(9):7610–7618
Raghunand N, Gatenby RA, Gillies RJ (2003) Microenvironmental and cellular consequences of altered blood flow in tumours. Br J Radiol 76(Spec 1):11–22
Holahan EV, Stuart PK, Dewey WC (1982) Enhancement of survival of CHO cells by acidic pH after x irradiation. Radiat Res 89(2):433–435
Freeman ML, Sierra E (1984) An acidic extracellular environment reduces the fixation of radiation damage. Radiat Res 97(1):154–161
Choi EK, Roberts KP, Griffin RJ, et al (2004) Effect of pH on radiation-induced p53 expression. Int J Radiat Oncol Biol Phys 60(4):1264–1271
Ojeda F, Skardova I, Guarda MI, et al (1996) Radiation-induced apoptosis in thymocytes: pH sensitization. Z Naturforsch 51(5–6):432–434 (Abstract)
Lee HS, Park HJ, Lyons JC, et al (1997) Radiation-induced apoptosis in different pH environments in vitro. Int J Radiat Oncol Biol Phys 38(5):1079–1087
Park H, Lyons JC, Griffin RJ, et al (2000) Apoptosis and cell cycle progression in an acidic environment after irradiation. Radiat Res 153(3):295–304
Park HJ, Lyons JC, Ohtsubo T, et al (2000) Cell cycle progression and apoptosis after irradiation in an acidic environment. Cell Death Differ 7(8):729–738
Ohtsubo T, Igawa H, Saito T, et al (2001) Acidic environment modifies heat- or radiation-induced apoptosis in human maxillary cancer cells. Int J Radiat Oncol Biol Phys 49(5):1391–1398
Park HJ, Lee SH, Chung H, et al (2003) Influence of environmental pH on G2-phase arrest caused by ionizing radiation. Radiat Res 159(1):86–93
Williams AC, Collard TJ, Paraskeva C (1999) An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines: implications for clonal selection during colorectal carcinogenesis. Oncogene 18(21):3199–3204
Schmaltz C, Hardenbergh PH, Wells A, et al (1998) Regulation of proliferation-survival decisions during tumor cell hypoxia. Mol Cell Biol 18(5):2845–2854
Pena LA, Fuks Z, Kolesnick R (1997) Stress-induced apoptosis and the sphingomyelin pathway. Biochem Pharmacol 53(5):615–621
Matsuyama S, Llopis J, Deveraux QL, et al (2000) Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis. Nat Cell Biol 2(6):318–325
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Hunter, A., Hendrikse, A., Renan, M. et al. Does the tumor microenvironment influence radiation-induced apoptosis?. Apoptosis 11, 1727–1735 (2006). https://doi.org/10.1007/s10495-006-9789-1
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DOI: https://doi.org/10.1007/s10495-006-9789-1