Skip to main content
SpringerLink
Log in

Iron Metabolism in Cancer and Infection

  • Chapter
  • First Online:
Iron Physiology and Pathophysiology in Humans

Part of the book series: Nutrition and Health ((NH))

Abstract

Progression through the G1, S, G2, and M phases of the cell cycle is regulated by sets of Cdks bound to corresponding cyclins (reviewed in [1]). Transition through the G1 phase is regulated by Cdk4/cyclin D1 and by Cdk6/cyclin D3. Cdk2/cyclin E is active at the late G1 phase and is responsible for the G1/S transition. Progression through the S phase is regulated by Cdk2/cyclin A. DNA synthesis during the S phase critically relies on the enzymatic activity of ribonucleotide reductase [2]. The S/G2 transition is regulated by Cdk1/cyclin A. Cdk1/cyclin B is responsible for the G2/M transition and for the completion of mitosis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol. 1997;13:261–291.

    Article  PubMed  CAS  Google Scholar 

  2. Tsimberidou AM, Alvarado Y, Giles FJ. Evolving role of ribonucleoside reductase inhibitors in hematologic malignancies. Expert Rev Anticancer Ther. 2002;2:437–448.

    Article  PubMed  CAS  Google Scholar 

  3. Green DA, Antholine WE, Wong SJ, Richardson DR, Chitambar CR. Inhibition of malignant cell growth by 311, a novel iron chelator of the pyridoxal isonicotinoyl hydrazone class: effect on the R2 subunit of ribonucleotide reductase. Clin Cancer Res. 2001;7:3574–3579.

    PubMed  CAS  Google Scholar 

  4. Richardson DR. Molecular mechanisms of iron uptake by cells and the use of iron chelators for the treatment of cancer. Curr Med Chem. 2005;12:2711–2729.

    Article  PubMed  CAS  Google Scholar 

  5. Coulonval K, Bockstaele L, Paternot S, Roger PP. Phosphorylations of cyclin-dependent kinase 2 revisited using two-dimensional gel electrophoresis. J Biol Chem. 2003;278:52052–52060.

    Article  PubMed  CAS  Google Scholar 

  6. Fu D, Richardson DR. Iron chelation and regulation of the cell-cycle: two mechanisms of post-transcriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion. Blood. 2007;110:752–761.

    Article  PubMed  CAS  Google Scholar 

  7. Yoon G, Kim HJ, Yoon YS, Cho H, Lim IK, Lee JH. Iron chelation-induced senescence-like growth arrest in hepatocyte cell lines: association of transforming growth factor beta1 (TGF-beta1)-mediated p27Kip1 expression. Biochem J. 2002;366:613–621.

    Article  PubMed  CAS  Google Scholar 

  8. Pahl PM, Reese SM, Horwitz LD. A lipid-soluble iron chelator alters cell cycle regulatory protein binding in breast cancer cells compared to normal breast cells. J Exp Ther Oncol. 2007;6:193–200.

    PubMed  CAS  Google Scholar 

  9. Debebe Z, Ammosova T, Jerebtsova M, et al. Iron chelators ICL670 and 311 inhibit HIV-1 transcription. Virology. 2007;367:324–33.

    Article  PubMed  CAS  Google Scholar 

  10. Wang G, Miskimins R, Miskimins WK. Regulation of p27(Kip1) by intracellular iron levels. Biometals. 2004;17:15–24.

    Article  PubMed  Google Scholar 

  11. Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE 2007;2007:cm8.

    Google Scholar 

  12. Gardner LB, Li Q, Park MS, Flanagan WM, Semenza GL, Dang CV. Hypoxia inhibits G1/S transition through regulation of p27 expression. J Biol Chem. 2001;276:7919–7926.

    Article  PubMed  CAS  Google Scholar 

  13. Horree N, Gort EH, van der Groep P, Heintz AP, Vooijs M, van Diest PJ. Hypoxia-inducible factor 1 alpha is essential for hypoxic p27 induction in endometrioid endometrial carcinoma. J Pathol. 2008;214:38–45.

    Article  PubMed  CAS  Google Scholar 

  14. Charles S, Ammosova T, Cardenas J, et al. Regulation of HIV-1 transcription at 3% versus 21% oxygen concentration. J Cell Physiol. 2009;221:469–479.

    Article  PubMed  CAS  Google Scholar 

  15. Pumfery A, de la Fuente C, Berro R, Nekhai S, Kashanchi F, Chao SH. Potential use of pharmacological cyclin-dependent kinase inhibitors as anti-HIV therapeutics. Curr Pharm Des. 2006;12:1949–1961.

    Article  PubMed  CAS  Google Scholar 

  16. Gao J, Richardson DR. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression. Blood. 2001;98:842–850.

    Article  PubMed  CAS  Google Scholar 

  17. Stevens RG, Jones DY, Micozzi MS, Taylor PR. Body iron stores and the risk of cancer. N Engl J Med. 1988;319:1047–1052.

    Article  PubMed  CAS  Google Scholar 

  18. Stevens RG, Graubard BI, Micozzi MS, Neriishi K, Blumberg BS. Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int J Cancer. 1994;56:364–369.

    Article  PubMed  CAS  Google Scholar 

  19. Oates PS, West AR. Heme in intestinal epithelial cell turnover, differentiation, detoxification, inflammation, carcinogenesis, absorption and motility. World J Gastroenterol. 2006;12:4281–4295.

    PubMed  CAS  Google Scholar 

  20. Hinoi T, Gesina G, Akyol A, et al. CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium. Gastroenterology. 2005;128:946–961.

    Article  PubMed  CAS  Google Scholar 

  21. Masson S, Chinn DJ, Tabaqchali MA, Waddup G, Dwarakanath AD. Is anaemia relevant in the referral and diagnosis of colorectal cancer? Colorectal Dis. 2007;9:736–739.

    Article  PubMed  CAS  Google Scholar 

  22. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician. 2007;75:671–678.

    PubMed  Google Scholar 

  23. Isaacson C, Bothwell TH, MacPhail AP, Simon M. The iron status of urban black subjects with carcinoma of the oesophagus. S Afr Med J. 1985;67:591–593.

    PubMed  CAS  Google Scholar 

  24. MacPhail AP, Simon MO, Torrance JD, Charlton RW, Bothwell TH, Isaacson C. Changing patterns of dietary iron overload in black South Africans. Am J Clin Nutr. 1979;32:1272–1278.

    PubMed  CAS  Google Scholar 

  25. Matsha T, Brink L, van Rensburg S, Hon D, Lombard C, Erasmus R. Traditional home-brewed beer consumption and iron status in patients with esophageal cancer and healthy control subjects from Transkei, South Africa. Nutr Cancer. 2006;56:67–73.

    Article  PubMed  CAS  Google Scholar 

  26. Kabat GC, Miller AB, Jain M, Rohan TE. A cohort study of dietary iron and heme iron intake and risk of colorectal cancer in women. Br J Cancer. 2007;97:118–122.

    Article  PubMed  CAS  Google Scholar 

  27. Knobel Y, Glei M, Osswald K, Pool-Zobel BL. Ferric iron increases ROS formation, modulates cell growth and enhances genotoxic damage by 4-hydroxynonenal in human colon tumor cells. Toxicol In Vitro. 2006;20:793–800.

    Article  PubMed  CAS  Google Scholar 

  28. Knobel Y, Weise A, Glei M, Sendt W, Claussen U, Pool-Zobel BL. Ferric iron is genotoxic in non-transformed and preneoplastic human colon cells. Food Chem Toxicol. 2007;45:804–811.

    Article  PubMed  CAS  Google Scholar 

  29. Ilsley JN, Belinsky GS, Guda K, et al. Dietary iron promotes azoxymethane-induced colon tumors in mice. Nutr Cancer. 2004;49:162–169.

    Article  PubMed  CAS  Google Scholar 

  30. Ko C, Siddaiah N, Berger J, et al. Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the national hemochromatosis transplant registry. Liver Int. 2007;27:1394–1401.

    Article  PubMed  Google Scholar 

  31. Hiatt T, Trotter JF, Kam I. Hepatocellular carcinoma in a noncirrhotic patient with hereditary hemochromatosis. Am J Med Sci. 2007;334:228–230.

    Article  PubMed  Google Scholar 

  32. Moyo VM, Makunike R, Gangaidzo IT, et al. African iron overload and hepatocellular carcinoma (HA-7-0-080). Eur J Haematol. 1998;60:28–34.

    Article  PubMed  CAS  Google Scholar 

  33. Gordeuk VR, McLaren CE, MacPhail AP, Deichsel G, Bothwell TH. Associations of iron overload in Africa with hepatocellular carcinoma and tuberculosis: Strachan’s 1929 thesis revisited. Blood. 1996;87:3470–3476.

    PubMed  CAS  Google Scholar 

  34. Mandishona E, MacPhail AP, Gordeuk VR, et al. Dietary iron overload as a risk factor for hepatocellular carcinoma in Black Africans. Hepatology. 1998;27:1563–1566.

    Article  PubMed  CAS  Google Scholar 

  35. Kew MC, Asare GA. Dietary iron overload in the African and hepatocellular carcinoma. Liver Int. 2007;27:735–741.

    Article  PubMed  CAS  Google Scholar 

  36. Asare GA, Bronz M, Naidoo V, Kew MC. Interactions between aflatoxin B1 and dietary iron overload in hepatic mutagenesis. Toxicology. 2007;234:157–166.

    Article  PubMed  CAS  Google Scholar 

  37. Ioannou GN, Weiss NS, Kowdley KV. Relationship between transferrin-iron saturation, alcohol consumption, and the incidence of cirrhosis and liver cancer. Clin Gastroenterol Hepatol. 2007;5:624–629.

    Article  PubMed  CAS  Google Scholar 

  38. Lehmann U, Wingen LU, Brakensiek K, et al. Epigenetic defects of hepatocellular carcinoma are already found in non-neoplastic liver cells from patients with hereditary haemochromatosis. Hum Mol Genet. 2007;16:1335–1342.

    Article  PubMed  CAS  Google Scholar 

  39. Furutani T, Hino K, Okuda M, et al. Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein. Gastroenterology. 2006;130:2087–2098.

    Article  PubMed  CAS  Google Scholar 

  40. Petrak J, Myslivcova D, Man P, et al. Proteomic analysis of hepatic iron overload in mice suggests dysregulation of urea cycle, impairment of fatty acid oxidation, and changes in the methylation cycle. Am J Physiol Gastrointest Liver Physiol. 2007;292:G1490–G1498.

    Article  PubMed  CAS  Google Scholar 

  41. Hucl T, Kylanpaa-Back ML, Witt H, et al. HFE genotypes in patients with chronic pancreatitis and pancreatic adenocarcinoma. Genet Med. 2007;9:479–483.

    Article  PubMed  Google Scholar 

  42. Kabat GC, Miller AB, Jain M, Rohan TE. Dietary iron and heme iron intake and risk of breast cancer: a prospective cohort study. Cancer Epidemiol Biomarkers Prev. 2007;16:1306–1308.

    Article  PubMed  CAS  Google Scholar 

  43. Hong CC, Ambrosone CB, Ahn J, et al. Genetic variability in iron-related oxidative stress pathways (Nrf2, NQ01, NOS3, and HO-1), iron intake, and risk of postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:1784–1794.

    Article  PubMed  CAS  Google Scholar 

  44. Calzolari A, Oliviero I, Deaglio S, et al. Transferrin receptor 2 is frequently expressed in human cancer cell lines. Blood Cells Mol Dis. 2007;39:82–91.

    Article  PubMed  CAS  Google Scholar 

  45. Kaomongkolgit R, Cheepsunthorn P, Pavasant P, Sanchavanakit N. Iron increases MMP-9 expression through activation of AP-1 via ERK/Akt pathway in human head and neck squamous carcinoma cells. Oral Oncol. 2008;44:587–594.

    Article  PubMed  CAS  Google Scholar 

  46. Becton DL, Bryles P. Deferoxamine inhibition of human neuroblastoma viability and proliferation. Cancer Res. 1988;48:7189–7192.

    PubMed  CAS  Google Scholar 

  47. Porter JB. Deferasirox: an effective once-daily orally active iron chelator. Drugs Today (Barc). 2006;42:623–637.

    Article  CAS  Google Scholar 

  48. Lescoat G, Chantrel-Groussard K, Pasdeloup N, Nick H, Brissot P, Gaboriau F. Antiproliferative and apoptotic effects in rat and human hepatoma cell cultures of the orally active iron chelator ICL670 compared to CP20: a possible relationship with polyamine metabolism. Cell Prolif. 2007;40:755–767.

    Article  PubMed  CAS  Google Scholar 

  49. Kalinowski DS, Richardson DR. Future of toxicology–iron chelators and differing modes of action and toxicity: the changing face of iron chelation therapy. Chem Res Toxicol. 2007;20:715–720.

    Article  PubMed  CAS  Google Scholar 

  50. Whitnall M, Howard J, Ponka P, Richardson DR. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci USA. 2006;103:14901–14906.

    Article  PubMed  CAS  Google Scholar 

  51. Kalinowski DS, Richardson DR. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol Rev. 2005;57:547–583.

    Article  PubMed  CAS  Google Scholar 

  52. Huynh C, Andrews NW. Iron acquisition within host cells and the pathogenicity of Leishmania. Cell Microbiol. 2008;10:293–300.

    Article  PubMed  CAS  Google Scholar 

  53. Chauvaux S, Rosso ML, Frangeul L, et al. Transcriptome analysis of Yersinia pestis in human plasma: an approach for discovering bacterial genes involved in septicaemic plague. Microbiology. 2007;153:3112–3124.

    Article  PubMed  CAS  Google Scholar 

  54. Chey WD, Wong BC. American college of gastroenterology guideline on the management of helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808–1825.

    Article  PubMed  CAS  Google Scholar 

  55. Vidakovics ML, Lamberti Y, Serra D, Berbers GA, van der Pol WL, Rodriguez ME. Iron stress increases Bordetella pertussis mucin-binding capacity and attachment to respiratory epithelial cells. FEMS Immunol Med Microbiol. 2007;51:414–421.

    Article  PubMed  CAS  Google Scholar 

  56. Mocny JC, Olson JS, Connell TD. Passively released heme from hemoglobin and myoglobin is a potential source of nutrient iron for Bordetella bronchiseptica. Infect Immun. 2007;75:4857–4866.

    Article  PubMed  CAS  Google Scholar 

  57. Murillo AC, Li HY, Alber T, et al. High throughput crystallography of TB drug targets. Infect Disord Drug Targets. 2007;7:127–139.

    Article  PubMed  CAS  Google Scholar 

  58. Gordeuk VR, Moyo VM, Nouraie M, et al. Circulating cytokines in pulmonary tuberculosis according to HIV status and dietary iron content. Int J Tuberc Lung Dis. 2009;13:1267–1273.

    PubMed  CAS  Google Scholar 

  59. Lounis N, Truffot-Pernot C, Grosset J, Gordeuk VR, Boelaert JR. Iron and Mycobacterium tuberculosis infection. J Clin Virol. 2001;20:123–126.

    Article  PubMed  CAS  Google Scholar 

  60. Boelaert JR, Vandecasteele SJ, Appelberg R, Gordeuk VR. The effect of the host’s iron status on tuberculosis. J Infect Dis. 2007;195:1745–1753.

    Article  PubMed  CAS  Google Scholar 

  61. Kasvosve I, Gomo ZA, Mvundura E, et al. Haptoglobin polymorphism and mortality in patients with tuberculosis. Int J Tuberc Lung Dis. 2000;4:771–775.

    PubMed  CAS  Google Scholar 

  62. Gangaidzo IT, Moyo VM, Mvundura E, et al. Association of pulmonary tuberculosis with increased dietary iron. J Infect Dis. 2001;184:936–939.

    Article  PubMed  CAS  Google Scholar 

  63. Monfeli RR, Beeson C. Targeting iron acquisition by Mycobacterium tuberculosis. Infect Disord Drug Targets. 2007;7:213–220.

    Article  PubMed  CAS  Google Scholar 

  64. Fujita N, Sugimoto R, Urawa N, et al. Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J Gastroenterol Hepatol. 2007;22:1886–1893.

    Article  PubMed  CAS  Google Scholar 

  65. Fujita N, Sugimoto R, Takeo M, et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med. 2007;13:97–104.

    Article  PubMed  CAS  Google Scholar 

  66. Taher A, Chamoun FM, Koussa S, et al. Efficacy and side effects of deferiprone (L1) in thalassemia patients not compliant with desferrioxamine. Acta Haematol. 1999;101:173–177.

    Article  PubMed  CAS  Google Scholar 

  67. Mlisana K, Auld SC, Grobler A, et al. Anaemia in acute HIV-1 subtype C infection. PLoS One. 2008;3:e1626.

    Article  PubMed  CAS  Google Scholar 

  68. Meyron-Holtz EG, Ghosh MC, Rouault TA. Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo. Science. 2004;306:2087–2090.

    Article  PubMed  CAS  Google Scholar 

  69. Atkuri KR, Herzenberg LA, Niemi AK, Cowan T. Importance of culturing primary lymphocytes at physiological oxygen levels. Proc Natl Acad Sci USA. 2007;104:4547–4552.

    Article  PubMed  CAS  Google Scholar 

  70. Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW. Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med. 2004;36:1–12.

    PubMed  Google Scholar 

  71. Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–275.

    Article  PubMed  CAS  Google Scholar 

  72. Salceda S, Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem. 1997;272:22642–22647.

    Article  PubMed  CAS  Google Scholar 

  73. Manalo DJ, Rowan A, Lavoie T, et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood. 2005;105:659–669.

    Article  PubMed  CAS  Google Scholar 

  74. Bagasra O, Steiner RM, Ballas SK, et al. Viral burden and disease progression in HIV-1-infected patients with sickle cell anemia. Am J Hematol. 1998;59:199–207.

    Article  PubMed  CAS  Google Scholar 

  75. Chen L, Xiong S, She H, Lin SW, Wang J, Tsukamoto H. Iron causes interactions of TAK1, p21ras, and phosphatidylinositol 3-kinase in caveolae to activate IkappaB kinase in hepatic macrophages. J Biol Chem. 2007;282:5582–5588.

    Article  PubMed  CAS  Google Scholar 

  76. Xiong S, She H, Takeuchi H, et al. Signaling role of intracellular iron in NF-kappaB activation. J Biol Chem. 2003;278:17646–17654.

    Article  PubMed  CAS  Google Scholar 

  77. Xiong S, She H, Tsukamoto H. Signaling role of iron in NF-kappa B activation in hepatic macrophages. Comp Hepatol. 2004;3(Suppl 1):S36.

    Article  PubMed  Google Scholar 

  78. Drakesmith H, Chen N, Ledermann H, Screaton G, Townsend A, Xu XN. HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. Proc Natl Acad Sci USA. 2005;102:11017–11022.

    Article  PubMed  CAS  Google Scholar 

  79. Gordeuk VR, Delanghe JR, Langlois MR, Boelaert JR. Iron status and the outcome of HIV infection: an overview. J Clin Virol. 2001;20:111–115.

    Article  PubMed  CAS  Google Scholar 

  80. Traore HN, Meyer D. The effect of iron overload on in vitro HIV-1 infection. J Clin Virol. 2004;31(Suppl 1):S92–S98.

    Article  PubMed  CAS  Google Scholar 

  81. Georgiou NA, van der Bruggen T, Oudshoorn M, Nottet HS, Marx JJ, van Asbeck BS. Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin. J Infect Dis. 2000;181:484–490.

    Article  PubMed  CAS  Google Scholar 

  82. Georgiou NA, van der Bruggen T, Oudshoorn M, Hider RC, Marx JJ, van Asbeck BS. Human immunodeficiency virus type 1 replication inhibition by the bidentate iron chelators CP502 and CP511 is caused by proliferation inhibition and the onset of apoptosis. Eur J Clin Invest. 2002;32(Suppl 1):91–96.

    Article  PubMed  CAS  Google Scholar 

  83. Sappey C, Boelaert JR, Legrand-Poels S, Forceille C, Favier A, Piette J. Iron chelation decreases NF-kappa B and HIV type 1 activation due to oxidative stress. AIDS Res Hum Retroviruses. 1995;11:1049–1061.

    Article  PubMed  CAS  Google Scholar 

  84. Li L, Frei B. Iron chelation inhibits NF-{kappa}B-mediated adhesion molecule expression by inhibiting p22phox protein expression and NADPH oxidase activity. Arterioscler Thromb Vasc Biol. 2006;26:2638–2643.

    Article  PubMed  CAS  Google Scholar 

  85. Nekhai S, Jeang K-T. Transcriptional and post-transcriptional regulation of HIV-1 gene expression: role of cellular factors for Tat and Rev. Future Microbiol. 2006;1:417–426.

    Article  PubMed  CAS  Google Scholar 

  86. Pereira LA, Bentley K, Peeters A, Churchill MJ, Deacon NJ. A compilation of cellular transcription factor interactions with the HIV-1 LTR promoter. Nucleic Acids Res. 2000;28:663–668.

    Article  PubMed  CAS  Google Scholar 

  87. Lassen K, Han Y, Zhou Y, Siliciano J, Siliciano RF. The multifactorial nature of HIV-1 latency. Trends Mol Med. 2004;10:525–531.

    Article  PubMed  CAS  Google Scholar 

  88. Williams SA, Kwon H, Chen LF, Greene WC. Sustained induction of NF-kappa B is required for efficient expression of latent human immunodeficiency virus type 1. J Virol. 2007;81:6043–6056.

    Article  PubMed  CAS  Google Scholar 

  89. Van Lint C, Quivy V, Demonte D, et al. Molecular mechanisms involved in HIV-1 transcriptional latency and reactivation: implications for the development of therapeutic strategies. Bull Mem Acad R Med Belg. 2004;159:176–189.

    PubMed  Google Scholar 

  90. Dingwall C, Ernberg I, Gait MJ, et al. Human immunodeficiency virus 1 tat protein binds trans-activation-responsive region (TAR) RNA in vitro. Proc Natl Acad Sci USA. 1989;86:6925–6929.

    Article  PubMed  CAS  Google Scholar 

  91. Feng S, Holland EC. HIV-1 tat trans-activation requires the loop sequence within tar. Nature. 1988;334:165–167.

    Article  PubMed  CAS  Google Scholar 

  92. Berkhout B, Jeang KT. Trans activation of human immunodeficiency virus type 1 is sequence specific for both the single-stranded bulge and loop of the trans-acting-responsive hairpin: a quantitative analysis. J Virol. 1989;63:5501–5504.

    PubMed  CAS  Google Scholar 

  93. Herrmann CH, Rice AP. Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor. J Virol. 1995;69:1612–1620.

    PubMed  CAS  Google Scholar 

  94. Yang X, Gold MO, Tang DN, et al. TAK, an HIV Tat-associated kinase, is a member of the cyclin-dependent family of protein kinases and is induced by activation of peripheral blood lymphocytes and differentiation of promonocytic cell lines. Proc Natl Acad Sci USA. 1997;94:12331–12336.

    Article  PubMed  CAS  Google Scholar 

  95. Zhu Y, Pe’ery T, Peng J, et al. Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. Genes Dev. 1997;11:2622–2632.

    Article  PubMed  CAS  Google Scholar 

  96. Garber ME, Wei P, Jones KA. HIV-1 Tat interacts with cyclin T1 to direct the P-TEFb CTD kinase complex to TAR RNA. Cold Spring Harb Symp Quant Biol. 1998;63:371–380.

    Article  PubMed  CAS  Google Scholar 

  97. Kiernan RE, Vanhulle C, Schiltz L, et al. HIV-1 tat transcriptional activity is regulated by acetylation. EMBO J. 1999;18:6106–6118.

    Article  PubMed  CAS  Google Scholar 

  98. Ott M, Schnolzer M, Garnica J, et al. Acetylation of the HIV-1 Tat protein by p300 is important for its transcriptional activity. Curr Biol. 1999;9:1489–1492.

    Article  PubMed  CAS  Google Scholar 

  99. Deng L, de la Fuente C, Fu P, et al. Acetylation of HIV-1 Tat by CBP/P300 increases transcription of integrated HIV-1 genome and enhances binding to core histones. Virology. 2000;277:278–295.

    Article  PubMed  CAS  Google Scholar 

  100. Liou LY, Herrmann CH, Rice AP. HIV-1 infection and regulation of Tat function in macrophages. Int J Biochem Cell Biol. 2004;36:1767–1775.

    Article  PubMed  CAS  Google Scholar 

  101. Liou LY, Herrmann CH, Rice AP. Human immunodeficiency virus type 1 infection induces cyclin T1 expression in macrophages. J Virol. 2004;78:8114–8119.

    Article  PubMed  CAS  Google Scholar 

  102. Nguyen VT, Kiss T, Michels AA, Bensaude O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature. 2001;414:322–325.

    Article  PubMed  CAS  Google Scholar 

  103. Yang Z, Zhu Q, Luo K, Zhou Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature. 2001;414:317–322.

    Article  PubMed  CAS  Google Scholar 

  104. Yik JH, Chen R, Nishimura R, Jennings JL, Link AJ, Zhou Q. Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. Mol Cell. 2003;12:971–982.

    Article  PubMed  CAS  Google Scholar 

  105. Michels AA, Nguyen VT, Fraldi A, et al. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Mol Cell Biol. 2003;23:4859–4869.

    Article  PubMed  CAS  Google Scholar 

  106. Kashanchi F, Agbottah ET, Pise-Masison CA, et al. Cell cycle-regulated transcription by the human immunodeficiency virus type 1 Tat transactivator. J Virol. 2000;74:652–660.

    Article  PubMed  CAS  Google Scholar 

  107. Nekhai S, Shukla RR, Fernandez A, Kumar A, Lamb NJ. Cell cycle-dependent stimulation of the HIV-1 promoter by Tat-associated CAK activator. Virology. 2000;266:246–256.

    Article  PubMed  CAS  Google Scholar 

  108. Nekhai S, Zhou M, Fernandez A, et al. HIV-1 Tat-associated RNA polymerase C-terminal domain kinase, CDK2, phosphorylates CDK7 and stimulates Tat-mediated transcription. Biochem J. 2002;364:649–657.

    Article  PubMed  CAS  Google Scholar 

  109. Deng L, Ammosova T, Pumfery A, Kashanchi F, Nekhai S. HIV-1 Tat interaction with RNA polymerase II C-terminal domain (CTD) and a dynamic association with CDK2 induce CTD phosphorylation and transcription from HIV-1 promoter. J Biol Chem. 2002;277:33922–33929.

    Article  PubMed  CAS  Google Scholar 

  110. Agbottah E, de La Fuente C, Nekhai S, et al. Antiviral activity of CYC202 in HIV-1-infected cells. J Biol Chem. 2005;280:3029–3042.

    Article  PubMed  CAS  Google Scholar 

  111. Ammosova T, Berro R, Kashanchi F, Nekhai S. RNA interference directed to CDK2 inhibits HIV-1 transcription. Virology. 2005;341:171–178.

    Article  PubMed  CAS  Google Scholar 

  112. Ammosova T, Berro R, Jerebtsova M, et al. Phosphorylation of HIV-1 Tat by CDK2 in HIV-1 transcription. Retrovirology. 2006;3:78.

    Article  PubMed  Google Scholar 

  113. Chakrabarti D, Schuster SM, Chakrabarti R. Cloning and characterization of subunit genes of ribonucleotide reductase, a cell-cycle-regulated enzyme, from Plasmodium falciparum. Proc Natl Acad Sci USA. 1993;90:12020–12024.

    Article  PubMed  CAS  Google Scholar 

  114. Rubin H, Salem JS, Li LS, et al. Cloning, sequence determination, and regulation of the ribonucleotide reductase subunits from Plasmodium falciparum: a target for antimalarial therapy. Proc Natl Acad Sci USA. 1993;90:9280–9284.

    Article  PubMed  CAS  Google Scholar 

  115. Krungkrai J, Cerami A, Henderson GB. Purification and characterization of dihydroorotate dehydrogenase from the rodent malaria parasite Plasmodium berghei. Biochemistry. 1991;30:1934–1939.

    Article  PubMed  CAS  Google Scholar 

  116. Bonday ZQ, Taketani S, Gupta PD, Padmanaban G. Heme biosynthesis by the malarial parasite. Import of delta-aminolevulinate dehydrase from the host red cell. J Biol Chem. 1997;272:21839–21846.

    Article  PubMed  CAS  Google Scholar 

  117. Krungkrai J, Krungkrai SR, Suraveratum N, Prapunwattana P. Mitochondrial ubiquinol-cytochrome c reductase and cytochrome c oxidase: chemotherapeutic targets in malarial parasites. Biochem Mol Biol Int. 1997;42:1007–1014.

    PubMed  CAS  Google Scholar 

  118. Petmitr S, Krungkrai J. Mitochondrial cytochrome b gene in two developmental stages of human malarial parasite plasmodium falciparum. Southeast Asian J Trop Med Public Health. 1995;26:600–605.

    PubMed  CAS  Google Scholar 

  119. Hodges M, Yikilmaz E, Patterson G, et al. An iron regulatory-like protein expressed in Plasmodium falciparum displays aconitase activity. Mol Biochem Parasitol. 2005;143:29–38.

    Article  PubMed  CAS  Google Scholar 

  120. Pouvelle B, Spiegel R, Hsiao L, et al. Direct access to serum macromolecules by intraerythrocytic malaria parasites. Nature. 1991;353:73–75.

    Article  PubMed  CAS  Google Scholar 

  121. Slater AF, Cerami A. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature. 1992;355:167–169.

    Article  PubMed  CAS  Google Scholar 

  122. Hershko C, Peto TE. Deferoxamine inhibition of malaria is independent of host iron status. J Exp Med. 1988;168:375–387.

    Article  PubMed  CAS  Google Scholar 

  123. Peto TE, Thompson JL. A reappraisal of the effects of iron and desferrioxamine on the growth of plasmodium falciparum ‘in vitro’: the unimportance of serum iron. Br J Haematol. 1986;63:273–280.

    Article  PubMed  CAS  Google Scholar 

  124. Gabay T, Ginsburg H. Hemoglobin denaturation and iron release in acidified red blood cell lysate–a possible source of iron for intraerythrocytic malaria parasites. Exp Parasitol. 1993;77:261–272.

    Article  PubMed  CAS  Google Scholar 

  125. Scholl PF, Tripathi AK, Sullivan DJ. Bioavailable iron and heme metabolism in Plasmodium falciparum. Curr Top Microbiol Immunol. 2005;295:293–324.

    Article  PubMed  CAS  Google Scholar 

  126. Burns ER, Pollack S. P. falciparum infected erythrocytes are capable of endocytosis. In Vitro Cell Dev Biol. 1988;24:481–486.

    Article  PubMed  CAS  Google Scholar 

  127. Loyevsky M, Lytton SD, Mester B, Libman J, Shanzer A, Cabantchik ZI. The antimalarial action of desferal involves a direct access route to erythrocytic (Plasmodium falciparum) parasites. J Clin Invest. 1993;91:218–224.

    Article  PubMed  CAS  Google Scholar 

  128. Loyevsky M, John C, Dickens B, Hu V, Miller JH, Gordeuk VR. Chelation of iron within the erythrocytic Plasmodium falciparum parasite by iron chelators. Mol Biochem Parasitol. 1999;101:43–59.

    Article  PubMed  CAS  Google Scholar 

  129. Scott MD, Ranz A, Kuypers FA, Lubin BH, Meshnick SR. Parasite uptake of desferroxamine: a prerequisite for antimalarial activity. Br J Haematol. 1990;75:598–602.

    Article  PubMed  CAS  Google Scholar 

  130. Darbari D, Loyevsky M, Gordeuk V, et al. Fluorescence measurements of the labile iron pool of sickle erythrocytes. Blood. 2003;102:357–364.

    Article  PubMed  CAS  Google Scholar 

  131. Galinski MR, Medina CC, Ingravallo P, Barnwell JW. A reticulocyte-binding protein complex of Plasmodium vivax merozoites. Cell. 1992;69:1213–1226.

    Article  PubMed  CAS  Google Scholar 

  132. Pasvol G, Weatherall DJ, Wilson RJ. The increased susceptibility of young red cells to invasion by the malarial parasite Plasmodium falciparum. Br J Haematol. 1980;45:285–295.

    Article  PubMed  CAS  Google Scholar 

  133. Prus E, Fibach E. The labile iron pool in human erythroid cells. Br J Haematol. 2008;142:301–307.

    Article  PubMed  Google Scholar 

  134. Hershko C, Graham G, Bates GW, Rachmilewitz EA. Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity. Br J Haematol. 1978;40:255–263.

    Article  PubMed  CAS  Google Scholar 

  135. Anuwatanakulchai M, Pootrakul P, Thuvasethakul P, Wasi P. Non-transferrin plasma iron in beta-thalassaemia/Hb E and haemoglobin H diseases. Scand J Haematol. 1984;32:153–158.

    Article  PubMed  CAS  Google Scholar 

  136. Batey RG, Lai Chung Fong P, Shamir S, Sherlock S. A non-transferrin-bound serum iron in idiopathic hemochromatosis. Dig Dis Sci. 1980;25:340–346.

    Article  PubMed  CAS  Google Scholar 

  137. Grootveld M, Bell JD, Halliwell B, Aruoma OI, Bomford A, Sadler PJ. Non-transferrin-bound iron in plasma or serum from patients with idiopathic hemochromatosis. Characterization by high performance liquid chromatography and nuclear magnetic resonance spectroscopy. J Biol Chem. 1989;264:4417–4422.

    PubMed  CAS  Google Scholar 

  138. Wang WC, Ahmed N, Hanna M. Non-transferrin-bound iron in long-term transfusion in children with congenital anemias. J Pediatr. 1986;108:552–557.

    Article  PubMed  CAS  Google Scholar 

  139. McNamara L, MacPhail AP, Mandishona E, et al. Non-transferrin-bound iron and hepatic dysfunction in African dietary iron overload. J Gastroenterol Hepatol. 1999;14:126–132.

    Article  PubMed  CAS  Google Scholar 

  140. Gutteridge JM, Rowley DA, Griffiths E, Halliwell B. Low-molecular-weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis. Clin Sci (Lond). 1985;68:463–467.

    CAS  Google Scholar 

  141. Baker E, Baker SM, Morgan EH. Characterisation of non-transferrin-bound iron (ferric citrate) uptake by rat hepatocytes in culture. Biochim Biophys Acta. 1998;1380:21–30.

    Article  PubMed  CAS  Google Scholar 

  142. Brissot P, Wright TL, Ma WL, Weisiger RA. Efficient clearance of non-transferrin-bound iron by rat liver. Implications for hepatic iron loading in iron overload states. J Clin Invest. 1985;76:1463–1470.

    Article  PubMed  CAS  Google Scholar 

  143. Link G, Pinson A, Hershko C. Heart cells in culture: a model of myocardial iron overload and chelation. J Lab Clin Med. 1985;106:147–153.

    PubMed  CAS  Google Scholar 

  144. Shindo M, Torimoto Y, Saito H, et al. Functional role of DMT1 in transferrin-independent iron uptake by human hepatocyte and hepatocellular carcinoma cell, HLF. Hepatol Res. 2006;35:152–162.

    PubMed  CAS  Google Scholar 

  145. Goma J, Renia L, Miltgen F, Mazier D. Iron overload increases hepatic development of Plasmodium yoelii in mice. Parasitology. 1996;112:165–168.

    Article  PubMed  CAS  Google Scholar 

  146. Loyevsky M, Sacci Jr JB, Boehme P, Weglicki W, John C, Gordeuk VR. Plasmodium falciparum and Plasmodium yoelii: effect of the iron chelation prodrug dexrazoxane on in vitro cultures. Exp Parasitol. 1999;91:105–114.

    Article  PubMed  CAS  Google Scholar 

  147. Stahel E, Mazier D, Guillouzo A, et al. Iron chelators: in vitro inhibitory effect on the liver stage of rodent and human malaria. Am J Trop Med Hyg. 1988;39:236–240.

    PubMed  CAS  Google Scholar 

  148. Sanchez-Lopez R, Haldar K. A transferrin-independent iron uptake activity in Plasmodium falciparum-infected and uninfected erythrocytes. Mol Biochem Parasitol. 1992;55:9–20.

    Article  PubMed  CAS  Google Scholar 

  149. Ekvall H, Arese P, Turrini F, et al. Acute haemolysis in childhood falciparum malaria. Trans R Soc Trop Med Hyg. 2001;95:611–617.

    Article  PubMed  CAS  Google Scholar 

  150. von Bonsdorff L, Lindeberg E, Sahlstedt L, Lehto J, Parkkinen J. Bleomycin-detectable iron assay for non-transferrin-bound iron in hematologic malignancies. Clin Chem. 2002;48:307–314.

    Google Scholar 

  151. Walter PB, Macklin EA, Porter J, et al. Inflammation and oxidant-stress in beta-thalassemia patients treated with iron chelators deferasirox (ICL670) or deferoxamine: an ancillary study of the Novartis CICL670A0107 trial. Haematologica. 2008;93:817–825.

    Article  PubMed  Google Scholar 

  152. Kartikasari AE, Georgiou NA, Visseren FL, van Kats-Renaud H, van Asbeck BS, Marx JJ. Endothelial activation and induction of monocyte adhesion by nontransferrin-bound iron present in human sera. FASEB J. 2006;20:353–355.

    PubMed  CAS  Google Scholar 

  153. Kartikasari AE, Georgiou NA, Visseren FL, van Kats-Renaud H, van Asbeck BS, Marx JJ. Intracellular labile iron modulates adhesion of human monocytes to human endothelial cells. Arterioscler Thromb Vasc Biol. 2004;24:2257–2262.

    Article  PubMed  CAS  Google Scholar 

  154. Tripathi AK, Sullivan DJ, Stins MF. Plasmodium falciparum-infected erythrocytes increase intercellular adhesion molecule 1 expression on brain endothelium through NF-kappaB. Infect Immun. 2006;74:3262–3270.

    Article  PubMed  CAS  Google Scholar 

  155. Gordeuk VR, Thuma PE, McLaren CE, et al. Transferrin saturation and recovery from coma in cerebral malaria. Blood. 1995;85:3297–3301.

    PubMed  CAS  Google Scholar 

  156. Raventos-Suarez C, Pollack S, Nagel RL. Plasmodium falciparum: inhibition of in vitro growth by desferrioxamine. Am J Trop Med Hyg. 1982;31:919–922.

    PubMed  CAS  Google Scholar 

  157. Scheibel LW, Adler A. Antimalarial activity of selected aromatic chelators. Mol Pharmacol. 1980;18:320–325.

    PubMed  CAS  Google Scholar 

  158. Heppner DG, Hallaway PE, Kontoghiorghes GJ, Eaton JW. Antimalarial properties of orally active iron chelators. Blood. 1988;72:358–361.

    PubMed  CAS  Google Scholar 

  159. Gordeuk VR, Thuma PE, Brittenham GM, et al. Iron chelation as a chemotherapeutic strategy for falciparum malaria. Am J Trop Med Hyg. 1993;48:193–197.

    PubMed  CAS  Google Scholar 

  160. Gordeuk VR, Thuma PE, Brittenham GM, et al. Iron chelation with desferrioxamine B in adults with asymptomatic Plasmodium falciparum parasitemia. Blood. 1992;79:308–312.

    PubMed  CAS  Google Scholar 

  161. Thuma PE, Olivieri NF, Mabeza GF, et al. Assessment of the effect of the oral iron chelator deferiprone on asymptomatic Plasmodium falciparum parasitemia in humans. Am J Trop Med Hyg. 1998;58:358–364.

    PubMed  CAS  Google Scholar 

  162. Bunnag D, Poltera AA, Viravan C, Looareesuwan S, Harinasuta KT, Schindlery C. Plasmodicidal effect of desferrioxamine B in human vivax or falciparum malaria from Thailand. Acta Trop. 1992;52:59–67.

    Article  PubMed  CAS  Google Scholar 

  163. Traore O, Carnevale P, Kaptue-Noche L, et al. Preliminary report on the use of desferrioxamine in the treatment of Plasmodium falciparum malaria. Am J Hematol. 1991;37:206–208.

    Article  PubMed  CAS  Google Scholar 

  164. Looareesuwan S, Wilairatana P, Vannaphan S, et al. Co-administration of desferrioxamine B with artesunate in malaria: an assessment of safety and tolerance. Ann Trop Med Parasitol. 1996;90:551–554.

    PubMed  CAS  Google Scholar 

  165. Thuma PE, Mabeza GF, Biemba G, et al. Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria. Trans R Soc Trop Med Hyg. 1998;92:214–218.

    Article  PubMed  CAS  Google Scholar 

  166. Gordeuk V, Thuma P, Brittenham G, et al. Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. N Engl J Med. 1992;327:1473–1477.

    Article  PubMed  CAS  Google Scholar 

  167. Sadrzadeh SM, Anderson DK, Panter SS, Hallaway PE, Eaton JW. Hemoglobin potentiates central nervous system damage. J Clin Invest. 1987;79:662–664.

    Article  PubMed  CAS  Google Scholar 

  168. van der Torn M, Thuma PE, Mabeza GF, et al. Loading dose of quinine in African children with cerebral malaria. Trans R Soc Trop Med Hyg. 1998;92:325–331.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Sickle Cell Disease, Division of Hematology and Oncology, Department of Medicine, Howard University, Washington, DC, USA

    Sergei Nekhai Ph.D.

  2. Sickle Cell Center, Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Victor R. Gordeuk M.D.

Authors
  1. Sergei Nekhai Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Victor R. Gordeuk M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Victor R. Gordeuk M.D. .

Editor information

Editors and Affiliations

  1. Bancroft Centre, Queensland Institute of Medical Research, Herston Road 300, Brisbane, 4029, Queensland, Australia

    Gregory J. Anderson

  2. Dept. Medicine &, Chao Family Comprehensive Cancer Ctr., University of California, Irvine, East 7th St. 5901, Long Beach, 90822, California, USA

    Gordon D. McLaren

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Nekhai, S., Gordeuk, V.R. (2012). Iron Metabolism in Cancer and Infection. In: Anderson, G., McLaren, G. (eds) Iron Physiology and Pathophysiology in Humans. Nutrition and Health. Humana Press. https://doi.org/10.1007/978-1-60327-485-2_24

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-485-2_24

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60327-484-5

  • Online ISBN: 978-1-60327-485-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation