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Hyperthermia: an effective strategy to induce apoptosis in cancer cells

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Abstract

Heat has been used as a medicinal and healing modality throughout human history. The combination of hyperthermia (HT) with radiation and anticancer agents has been used clinically and has shown positive results to a certain extent. However, the clinical results of HT treatment alone have been only partially satisfactory. Cell death following HT treatment is a function of both temperature and treatment duration. HT induces cancer cell death through apoptosis; the degree of apoptosis and the apoptotic pathway vary in different cancer cell types. HT-induced reactive oxygen species production are responsible for apoptosis in various cell types. However, the underlying mechanism of signal transduction and the genes related to this process still need to be elucidated. In this review, we summarize the molecular mechanism of apoptosis induced by HT, enhancement of heat-induced apoptosis, and the genetic network involved in HT-induced apoptosis.

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References

  1. Brade AM, Szmitko P, Ngo D, Liu FF, Klamut HJ (2003) Heat-directed suicide gene therapy for breast cancer. Cancer Gene Ther 10:294–301

    Article  CAS  PubMed  Google Scholar 

  2. Reinhold HS, Endrich B (1986) Tumor microcirculation as a target for hyperthermia. Int J Hyperthermia 2:111–137

    Article  CAS  PubMed  Google Scholar 

  3. Song VE, Choi IB, Nah BS et al (1995) Microvasculature and perfusion in normal tissues and tumours. In: Seegenschmiedt MH, Fessenden P, Vernon CC (eds) Thermoradiotherapy and thermochemotherapy, vol 1. Springer, Berlin, pp 139–156

    Chapter  Google Scholar 

  4. Vaupel PW, Kelleher DK (1995) Metabolic status and reaction to heat of normal and tumor tissue. In: Seegenschmiedt MH, Fessenden P, Vernon CC (eds) Thermoradiotherapy and thermochemotherapy, vol 1. Springer, Berlin, pp 157–176

    Chapter  Google Scholar 

  5. Raaphorst GP (1990) Fundamental aspects of hyperthermic biology. In: Field SB, Hand JW (eds) An introduction to the practical aspects of clinical hyperthermia. Taylor and Francis, London, pp 10–54

    Google Scholar 

  6. Fajardo LF (1984) Pathological effects of hyperthermia in normal tissues. Cancer Res 44:4826s–4835s

    CAS  PubMed  Google Scholar 

  7. Sminia P, Van der Zee J, Wondergem J, Haveman J (1994) Effect of hyperthermia on the central nervous system: a review. Int J Hyperthermia 10:1–130

    Article  CAS  PubMed  Google Scholar 

  8. Jones EL, Oleson JR, Prpsnitz LR et al (2005) Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol 23:307–385

    Google Scholar 

  9. Plati J, Bucur O, Khosravi FR (2011) Apoptotic cell signaling in cancer progression and therapy. Integr Biol 3:279–296

    Article  CAS  Google Scholar 

  10. Sankari SL, Masthan KMK, Babu NA, Bhattacharjee T, Elumalai M (2012) Apoptosis in cancer—an update. Asian Pac J Cancer Prev 10:4873–4878

    Article  Google Scholar 

  11. Welch WJ, Suhan JP (1985) Morphological study of the mammalian stress response: characterization of changes in cytoplasmic organelles, cytoskeleton, and nucleoli, and appearance of intranuclear actin filaments in rat fibroblasts after heat-shock treatment. J Cell Biol 101:1198–1211

    Article  CAS  PubMed  Google Scholar 

  12. Richter K, Haslbeck M, Buchner J (2010) The heat shock response: life on the verge of death. Mol Cell 40:253–256

    Article  CAS  PubMed  Google Scholar 

  13. Pollard TD (2003) The cytoskeleton, cellular motility and the reductionist agenda. Nature 422:741–745

    Article  CAS  PubMed  Google Scholar 

  14. Armour EP, McEachern D, Wang Z, Corry PM, Martinez A (1993) Sensitivity of human cells to mild hyperthermia. Cancer Res 53:2740–2744

    CAS  PubMed  Google Scholar 

  15. Huang SH, Yang KJ, Wu JC, Chang KJ, Wang SM (1999) Effects of hyperthermia on the cytoskeleton and focal adhesion proteins in a human thyroid carcinoma cell line. J Cell Biochem 75:327–337

    Article  CAS  PubMed  Google Scholar 

  16. Pawlik A, Nowak JM, Grzanka D, Gackowska L, Michalkiewicz J, Grzanka A (2013) Hyperthermia induces cytoskeletal alterations and mitotic catastrophe in p53-deficient H1299 lung cancer cells. Acta Histochem 115:8–15

    Article  CAS  PubMed  Google Scholar 

  17. Sharma SK, Christen P, Goloubinoff P (2009) Disaggregating chaperones: an unfolding story. Curr Protein Pept Sci 10:432–446

    Article  CAS  PubMed  Google Scholar 

  18. Hartl FU (1996) Molecular chaperone in cellular protein folding. Nature 13:571–579

    Article  Google Scholar 

  19. Csermely P (2001) Chaperone overload as a possible contributor to civilization diseases. Trends Genet 17:701–704

    Article  CAS  PubMed  Google Scholar 

  20. Sreedhar AS, Csermely P (2004) Heat shock proteins in the regulation of apoptosis: new strategies in tumor therapy. A comprehensive review. Pharmacol Ther 101:227–257

    Article  CAS  PubMed  Google Scholar 

  21. Hildebrandt B, Wust P, Ahlers O et al (2002) The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol 43:33–56

    Article  PubMed  Google Scholar 

  22. Furusawa Y, Iizumi T, Fujiwara Y et al (2012) Inhibition of checkpoint kinase 1 abrogates G2/M checkpoint activation and promotes apoptosis under heat stress. Apoptosis 17:102–112

    Article  CAS  PubMed  Google Scholar 

  23. Turner T, Caspari T (2014) When heat casts a spell on the DNA damage checkpoints. Open Biol 4:140008

    Article  PubMed Central  PubMed  Google Scholar 

  24. Velichko AK, Petrova NV, Kantidze OL, Razin SV (2012) Dual effect of heat shock on DNA replication and genome integrity. Mol Biol Cell 23:3450–3460

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Bonzon C, Bouchier-Hayes L, Pagliari LJ, Green DR, Newmeyer DD (2006) Caspase-2-induced apoptosis requires bid cleavage: a physiological role for bid in heat shock-induced death. Mol Biol Cell 17:2150–2157

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Ho LH, Read SH, Dorstyn L, Lambrusco L, Kumar S (2008) Caspase-2 is required for cell death induced by cytoskeletal disruption. Oncogene 27:3393–3404

    Article  CAS  PubMed  Google Scholar 

  27. Bouchier-Hayes L, Oberst A, McStay GP, Connell S, Tait SW et al (2009) Characterization of cytoplasmic caspase-2 activation by induced proximity. Mol Cell 35:830–840

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Tu S, McStay GP, Boucher LM, Mak T, Beere HM et al (2006) In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis. Nat Cell Biol 8:72–77

    Article  CAS  PubMed  Google Scholar 

  29. Pagliari LJ, Kuwana T, Bonzon C, Newmeyer DD, Tu S et al (2005) The multidomain proapoptotic molecules Bax and Bak are directly activated by heat. Proc Natl Acad Sci USA 102:17975–17980

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Shelton SN, Dillard CD, Robertson JD (2010) Activation of caspase-9, but not caspase-2 or caspase-8, is essential for heat-induced apoptosis in Jurkat cells. J Biol Chem 285:40525–40533

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Mahajan IM, Chen MD, Muro I, Robertson JD, Wright CW, Bratton SB (2014) BH3-only protein BIM mediates heat shock-induced apoptosis. PLoS One 9:e84388

    Article  PubMed Central  PubMed  Google Scholar 

  32. Kuwana T, Bouchier-Hayes L, Chipuk JE et al (2005) BH3 domains of BH3-only proteins differentially regulates Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17:525–535

    Article  CAS  PubMed  Google Scholar 

  33. Puthalakath H, Huang DC, OReilly LA, King SM, Strasser A (1999) The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 3:287–296

    Article  CAS  PubMed  Google Scholar 

  34. Cui ZG, Piao JL, Rehman MU et al (2014) Molecular mechanisms of hyperthermia-induced apoptosis enhanced by withaferin A. Eur J Pharmacol 723:99–107

    Article  CAS  PubMed  Google Scholar 

  35. Hirano H, Tabuchi Y, Kondo T et al (2005) Analysis of gene expression in apoptosis of human lymphoma U937 cells induced by heat shock and the effects of α-phenyl N-tert-butylnitrone (PBN) and its derivatives. Apoptosis 10:331–340

    Article  CAS  PubMed  Google Scholar 

  36. Reap EA, Roof K, Maynor K, Borrero M, Booker J, Cohen PL (1997) Radiation and stress-induced apoptosis: a role for Fas/Fas ligand interactions. Proc Natl Acad Sci USA 94:5750–5755

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Tran SEF, Meinander A, Holmström TH et al (2003) Heat stress downregulates FLIP and sensitizes cells to Fas receptor-mediated apoptosis. Cell Death Differ 10:1137–1147

    Article  CAS  PubMed  Google Scholar 

  38. Yu DY, Matsuya Y, Zhao QL et al (2008) Enhancement of hyperthermia-induced apoptosis by a new synthesized class of benzocycloalkene compounds. Apoptosis 13:448–461

    Article  CAS  PubMed  Google Scholar 

  39. Kelley SK, Harris LA, Xie D, Deforge L, Totpal K, Bussiere J, Fox JA (2001) Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. J Pharmacol Exp Ther 299:31–38

    CAS  PubMed  Google Scholar 

  40. Kato S, Sadarangani A, Lange S, Villalon M, Branes J, Brosens JJ, Owen GI, Cuello M (2007) The oestrogen metabolite 2-methoxyoestradiol alone or in combination with tumor necrosis factor-related apoptosis-inducing ligand mediates apoptosis in cancerous but not healthy cells of the human endometrium. Endocr Relat Cancer 14:351–368

    Article  CAS  PubMed  Google Scholar 

  41. Gonzalvez F, Ashkenazi A (2010) New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 29:4752–4765

    Article  CAS  PubMed  Google Scholar 

  42. Alcala MA Jr, Park K, Yoo J, Lee DH, Park BH, Lee BC, Bartlett DL, Lee YJ (2010) Effect of hyperthermia in combination with TRAIL on the JNK-Bim signal transduction pathway and growth of xenograft tumors. J Cell Biochem 110:1073–1081

    Article  PubMed Central  PubMed  Google Scholar 

  43. Yoo J, Lee Y (2007) Effect of hyperthermia on TRAIL-induced apoptotic death in human colon cancer cells: development of a novel strategy for regional therapy. J Cell Biochem 101:619–630

    Article  CAS  PubMed  Google Scholar 

  44. Schett G, Steiner C-W, Xu Q, Smolen JS, Steiner G (2003) TNFα mediates susceptibility to heat-induced apoptosis by protein phosphatase-mediated inhibition of the HSF1/hsp70 stress response. Cell Death Differ 10:1126–1136

    Article  CAS  PubMed  Google Scholar 

  45. Imao M, Nagaki M, Moriwaki H (2006) Dual effects of heat stress on tumor necrosis factor-α-induced hepatocyte apoptosis in mice. Lab Invest 86:959–967

    Article  CAS  PubMed  Google Scholar 

  46. Han J, Back SH, Hur J et al (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 15:481–490

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Li FJ, Kondo T, Zhao QL, Tanabe K, Ogawa R, Li M, Arai Y (2001) Enhancement of hyperthermia-induced apoptosis by a free radical initiator, 2,2′-azobis (2-amidinopropane) dihydrochloride, in human histiocytic lymphoma U937 cells. Free Radic Res 35:281–299

    Article  CAS  PubMed  Google Scholar 

  48. Hou CH, Lin FL, Hou SM, Liu JF (2014) Hyperthermia induces apoptosis through endoplasmic reticulum and reactive oxygen species in human osteosarcoma cells. Int J Mol Sci 15:17380–173095

    Article  PubMed Central  PubMed  Google Scholar 

  49. Cui ZG, Kondo T, Matsumoto H (2006) Enhancement of apoptosis by nitric oxide released from alpha-phenyl-tert-butyl nitrone under hyperthetmic conditions. J Cell Physiol 206:468–476

    Article  CAS  PubMed  Google Scholar 

  50. Bolisetty S, Jaimes EA (2013) Mitochondria and reactive oxygen species: physiology and pathophysiology. Int J Mol Sci 14:6306–6344

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Zhao QL, Fujiwara Y, Kondo T (2006) Mechanism of cell death induction by nitroxide and hyperthermia. Free Radic Biol Med 40:1131–1143

    Article  CAS  PubMed  Google Scholar 

  52. Ahmed K, Zhao QL, Matsuya Y, Yu DY, Salunga TL, Nemoto H, Kondo T (2007) Enhancement of macrospheloid induced apoptosis by mild hyperthermia. Int J Hyperthermia 23:353–361

    Article  CAS  PubMed  Google Scholar 

  53. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 555:335–344

    Article  Google Scholar 

  54. El-Orabi NF, Rogers C, Edwards HG, Schwartz DD (2011) Heat-induced inhibition of superoxide dismutase and accumulation of reactive oxygen species leads to HT-22 neuronal cell death. J Thermal Biol 36:49–56

    Article  CAS  Google Scholar 

  55. Beckman JS, Koppenol WH (1996) Nitric oxide superoxide and peroxynitrite: the good the bad and the ugly. Am J Physiol 271:C1424–C1437

    CAS  PubMed  Google Scholar 

  56. Yoshihisa Y, Zhao QL, Hassan MA et al (2011) SOD/catalase mimetic platinum nanoparticles inhibit heat-induced apoptosis in human lymphoma U937 and HH cells. Free Radic Res 45:326–335

    Article  CAS  PubMed  Google Scholar 

  57. Slimen IB, Najar T, Ghram A, Dabbebi H, Mrad MB, Abdrabbah M (2014) Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review. Int J Hyperthermia 30:513–523

    Article  PubMed  Google Scholar 

  58. Yu DY, Zhao QL, Wei ZL, Ahmed K, Shehata M, Kondo T (2009) Enhancement of hyperthermia-induced apoptosis by sanazole in human lymphoma U937 cells. Int J Hyperthermia 25:364–373

    Article  CAS  PubMed  Google Scholar 

  59. Kameda K, Kondo T, Tanabe K, Zhao QL, Seto H (2001) The role of intracellular Ca2+ in apoptosis induced by hyperthermia and its enhancement by verapamil in U937 cells. Int J Radiat Oncol Biol Phys 49:1369–1379

    Article  CAS  PubMed  Google Scholar 

  60. Arai Y, Kondo T, Tanabe K et al (2002) Enhancement of hyperthermia-induced apoptosis by local anesthetics on human histiocytic lymphoma U937 cells. J Biol Chem 277:18986–18993

    Article  CAS  PubMed  Google Scholar 

  61. Wada S, Cui ZG, Kondo T et al (2005) A hydrogen peroxide-generating agent, 6-formylpterin, enhances heat-induced apoptosis. Int J Hyperthermia 21:231–246

    Article  CAS  PubMed  Google Scholar 

  62. Yu DY, Matsuya Y, Zhao QL et al (2007) Enhancement of hyperthermia-induced apoptosis by a new synthesized class of furan-fused tetracyclic compounds. Apoptosis 12:1523–1532

    Article  CAS  PubMed  Google Scholar 

  63. Wei ZL, Zhao QL, Yu DY, Hassan MA, Kondo T (2008) Enhancement of sodium butyrate-induced cell death by hyperthermia in HCT 116 human colorectal cancer cells. Anticancer Res 28:1693–1700

    CAS  PubMed  Google Scholar 

  64. Cui ZG, Piao JL, Kondo T et al (2014) Molecular mechanisms of hyperthermia-induced apoptosis enhanced by docosahexaenoic acid: implication for cancer therapy. Chem Biol Interact 215:46–53

    Article  CAS  PubMed  Google Scholar 

  65. Schildkopf P, Ott OJ, Frey B, Wadepohl M, Sauer R, Fietkau R et al (2010) Biological rationales and clinical applications of temperature controlled hyperthermia—implications for multimodal cancer treatments. Curr Med Chem 17:3045–3057

    Article  CAS  PubMed  Google Scholar 

  66. Ihara M, Takeshita S, Okaichi K, Okumura Y, Ohnishi T (2014) Heat exposure enhances radiosensitivity by depressing DNA-PK kinase activity during double strand break repair. Int J Hyperthermia 30:102–109

    Article  CAS  PubMed  Google Scholar 

  67. Hori T, Kondo T, Lee H, Song CW, Park HJ (2011) Hyperthermia enhances the effect of β-lapachone to cause γH2AX formations and cell death in human osteosarcoma cells. Int J Hyperthermia 27:52–63

    Article  Google Scholar 

  68. Tabuchi Y, Wada S, Furusawa Y, Ohtuska K, Kondo T (2012) Gene networks related to the cell death elicited by hyperthermia in human oral squamous cell carcinoma HSC-3 cells. Int J Mol Med 29:380–386

    CAS  PubMed  Google Scholar 

  69. Kariya A, Tabuchi Y, Yunoki T, Kondo T (2013) Identification of common gene networks responsive to mild hyperthermia in human cancer cells. Int J Mol Med 32:195–202

    CAS  PubMed  Google Scholar 

  70. Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918

    Article  CAS  PubMed  Google Scholar 

  71. Yunoki T, Kariya A, Kondo T, Hayashi A, Tabuchi Y (2013) The combination of silencing BAG3 and inhibition of the JNK pathway enhances hyperthermia sensitivity in human oral squamous cell carcinoma cells. Cancer Lett 335:52–57

    Article  CAS  PubMed  Google Scholar 

  72. Wada S, Tabuchi Y, Kondo T et al (2007) Gene expression in enhanced apoptosis of human lymphoma U937 cells treated with the combination of different free radical generators and hyperthermia. Free Radic Res 41:73–81

    Article  CAS  PubMed  Google Scholar 

  73. Tabuchi Y, Takasaki I, Wada S et al (2008) Genes and genetic networks responsive to mild hyperthermia in human lymphoma U937 cells. Int J Hyperthermia 24:613–622

    Article  CAS  PubMed  Google Scholar 

  74. Furusawa Y, Tabuchi Y, Takasaki I, Wada S, Ohtsuka K, Kondo T (2009) Gene networks involved in apoptosis induced by hyperthermia in human lymphoma U937 cells. Cell Biol Int 33:1253–1262

    Article  CAS  PubMed  Google Scholar 

  75. Furusawa Y, Tabuchi Y, Wada S, Takasaki I, Ohtsuka K, Kondo T (2011) Identification of biological functions and gene networks regulated by heat stress in U937 human lymphoma cells. Int J Mol Med 28:143–151

    CAS  PubMed  Google Scholar 

  76. Tabuchi Y, Furusawa Y, Kondo T (2011) Genes and gene networks in the apoptosis induced by heat stress in human leukemia U937 cells. Thermal Med 27:31–40

    Article  Google Scholar 

  77. Kaur P, Hurwitz MD, Krishnan S, Asea A (2011) Combined hyperthermia and radiotherapy for the treatment of cancer. Cancers 3:3799–3823

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Ahmed Bettaieb, Paulina K. Wrzal and Diana A. Averill-Bates (2013) In: Letícia Rangel (ed) Hyperthermia: cancer treatment and beyond, cancer treatment—conventional and innovative approaches. InTech. doi:10.5772/55795

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Acknowledgments

This work was supported by Japan Society for the Promotion of Science Grant-in-Aid for Challenging Exploratory Research (No. 26670551).

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Authors and Affiliations

  1. Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan

    Kanwal Ahmed & Takashi Kondo

  2. Division of Molecular Genetic Research, Life Science Research Center, University of Toyama, Toyama, 930-0194, Japan

    Yoshiaki Tabuchi

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  1. Kanwal Ahmed
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Correspondence to Takashi Kondo.

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Ahmed, K., Tabuchi, Y. & Kondo, T. Hyperthermia: an effective strategy to induce apoptosis in cancer cells. Apoptosis 20, 1411–1419 (2015). https://doi.org/10.1007/s10495-015-1168-3

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