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Combined Thermotherapy and Heat Shock Protein Modulation for Tumor Treatment

Part of the Heat Shock Proteins book series (HESP,volume 21)

Abstract

Introduction

Thermal therapy (hyperthermia) holds a promising treatment for tumor-affected patients particularly those with surgery intolerance. Recent advances and clinical trials for therapeutic purposes of heat shock proteins (Hsp) inhibitors and the astonishing progress in the field of nanotechnology pave the way for novel strategies for combined and effective treatment and targeting of the tumor cells. In here, we highlight the history of hyperthermia, as a therapeutic tool for tumors, and provide the state-of-the-art regarding the promising synergism between hyperthermia, HSP modulation and the targeted nanoparticles for tumor cell targeted therapy.

Methods

A literature based collection of articles in the available search engines (PubMed and Google Scholar).

Results

We show the possible combination of thermal therapy together with Hsp inhibitors for treating cancers.

Conclusions

The use of Hsp inhibitors potentiates the cytotoxic and/or anti-proliferative effects of the hyperthermia.

Keywords

  • HSP
  • HSP inhibitors
  • Hyperthermia
  • Nanoparticles
  • Exosomes
  • Tumor treatment

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Fig. 1
Fig. 2
Fig. 3

Abbreviations

CRC:

colorectal cancer

ECM:

extracellular matrix

HIF:

hypoxia inducible factors

HSP:

heat shock protein/s

MRI:

magnetic resonance imaging

MSC:

mesenchymal stem cells

siRNA:

small interfering RNA

SPIONs:

superparamagnetic iron oxide nanoparticles

References

  1. Glazer ES, Curley SA (2011) The ongoing history of thermal therapy for cancer. Surg Oncol Clin N Am 20:229–235, vii

    PubMed  CrossRef  Google Scholar 

  2. Mellal I, Oukaira A, Kengene E, Lakhssassi A (2017) Thermal therapy modalities for cancer treatment: a review and future perspectives. Int J Appl Sci – Res Rev 04:14

    CrossRef  Google Scholar 

  3. van der Zee J (2002) Heating the patient: a promising approach? Ann Oncol 13:1173–1184

    PubMed  CrossRef  Google Scholar 

  4. Toraya-Brown S, Fiering S (2014) Local tumour hyperthermia as immunotherapy for metastatic cancer. Int J Hyperth 30:531–539

    CAS  CrossRef  Google Scholar 

  5. Skitzki JJ, Repasky EA, Evans SS (2009) Hyperthermia as an immunotherapy strategy for cancer. Curr Opin Investig Drugs 10:550–558

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hildebrandt B, Wust P, Ahlers O, Dieing A, Sreenivasa G, Kerner T, Felix R, Riess H (2002) The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol 43:33–56

    PubMed  CrossRef  Google Scholar 

  7. Wust P, Hildebrandt B, Sreenivasa G, Rau B, Gellermann J, Riess H, Felix R, Schlag PM (2002) Hyperthermia in combined treatment of cancer. Lancet Oncol 3:487–497

    CAS  PubMed  CrossRef  Google Scholar 

  8. Falk MH, Issels RD (2001) Hyperthermia in oncology. Int J Hyperth 17:1–18

    CAS  CrossRef  Google Scholar 

  9. Ohtsuka K (1986) Thermotolerance in normal and tumor tissues. Gan No Rinsho Jpn J Cancer Clin 32:1671–1677

    CAS  Google Scholar 

  10. Urano M (1986) Kinetics of thermotolerance in normal and tumor tissues: a review. Cancer Res 46:474–482

    CAS  PubMed  Google Scholar 

  11. Carper SW, Duffy JJ, Gerner EW (1987) Heat shock proteins in thermotolerance and other cellular processes. Cancer Res 47:5249–5255

    CAS  PubMed  Google Scholar 

  12. Kosaka M, Othman T, Matsumoto T, Ohwatari N (1998) Heat shock proteins: roles in thermotolerance and as molecular targets for cancer therapy. Therm Med (Jpn J Hyperth Oncol) 14:170–188

    CrossRef  Google Scholar 

  13. van den Tempel N, Horsman MR, Kanaar R (2016) Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms. Int J Hyperth 32:446–454

    CrossRef  CAS  Google Scholar 

  14. Dings RP, Loren ML, Zhang Y, Mikkelson S, Mayo KH, Corry P, Griffin RJ (2011) Tumour thermotolerance, a physiological phenomenon involving vessel normalisation. Int J Hyperth 27:42–52

    CrossRef  Google Scholar 

  15. Geiser F (2010) Aestivation in mammals and birds. In: Arturo Navas C, Carvalho J (eds) Aestivation. Progress in molecular and subcellular biology, vol 49. Springer, Berlin/Heidelberg, pp 95–111

    Google Scholar 

  16. Staples JF (2016) Metabolic flexibility: hibernation, torpor, and estivation. Compr Physiol 6:737–771

    PubMed  CrossRef  Google Scholar 

  17. Saadeldin IM, Swelum AA-A, Elsafadi M, Mahmood A, Alfayez M, Alowaimer AN (2018) Differences between the tolerance of camel oocytes and cumulus cells to acute and chronic hyperthermia. J Therm Biol 74:47–54

    PubMed  CrossRef  Google Scholar 

  18. Saadeldin IM, Swelum AA-A, Noreldin AE, Tukur HA, Abdelazim AM, Abomughaid MM, Alowaimer AN (2019b) Isolation and culture of skin-derived Differentiated and stem-like cells obtained from the arabian camel (Camelus dromedarius). Animals 9:378

    CrossRef  PubMed Central  Google Scholar 

  19. Saadeldin IM, Swelum AA-A, Tukur HA, Alowaimer AN (2019c) Thermotolerance of camel (Camelus dromedarius) somatic cells affected by the cell type and the dissociation method. Environ Sci Pollut Res 26(28):29490–29496

    CAS  CrossRef  Google Scholar 

  20. Song AS, Najjar AM, Diller KR (2014) Thermally induced apoptosis, necrosis, and heat shock protein expression in three-dimensional culture. J Biomech Eng 136:071006

    CrossRef  Google Scholar 

  21. Gong YN, Crawford JC, Heckmann BL, Green DR (2018) To the edge of cell death and back. FEBS J 286:430–440

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  22. Saadeldin IM, Abdel-Aziz Swelum A, Elsafadi M, Mahmood A, Osama A, Shikshaky H, Alfayez M, Alowaimer AN, Magdeldin S (2019a) Thermotolerance and plasticity of camel somatic cells exposed to acute and chronic heat stress. J Adv Res 22:105–118

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  23. Sun G, Guzman E, Balasanyan V, Conner CM, Wong K, Zhou HR, Kosik KS, Montell DJ (2017) A molecular signature for anastasis, recovery from the brink of apoptotic cell death. J Cell Biol 216:3355–3368

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  24. Tang HL, Tang HM, Mak KH, Hu S, Wang SS, Wong KM, Wong CST, Wu HY, Law HT, Liu K et al (2012) Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. Mol Biol Cell 23:2240–2252

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  25. Tang HM, Tang HL (2018) Anastasis: recovery from the brink of cell death. R Soc Open Sci 5:180442

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  26. Raj AT, Kheur S, Bhonde R, Gupta AA, Patil VR, Kharat A (2019) Potential role of anastasis in cancer initiation and progression. Apoptosis 24:383–384

    PubMed  CrossRef  Google Scholar 

  27. Chatterjee S, Burns TF (2017) Targeting heat shock proteins in cancer: a promising therapeutic approach. Int J Mol Sci 18:1978

    PubMed Central  CrossRef  CAS  Google Scholar 

  28. Khaleque MA, Bharti A, Sawyer D, Gong J, Benjamin IJ, Stevenson MA, Calderwood SK (2005) Induction of heat shock proteins by heregulin beta1 leads to protection from apoptosis and anchorage-independent growth. Oncogene 24:6564–6573

    CAS  PubMed  CrossRef  Google Scholar 

  29. Neckers L (2006) Chaperoning oncogenes: Hsp90 as a target of geldanamycin. Handb Exp Pharmacol 172:259–277

    CAS  CrossRef  Google Scholar 

  30. Gong J, Weng D, Eguchi T, Murshid A, Sherman MY, Song B, Calderwood SK (2015) Targeting the Hsp70 gene delays mammary tumor initiation and inhibits tumor cell metastasis. Oncogene 34:5460–5471

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  31. Bykov VJN, Eriksson SE, Bianchi J, Wiman KG (2018) Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer 18:89–102

    CAS  PubMed  CrossRef  Google Scholar 

  32. Pinhasi-Kimhi O, Michalovitz D, Ben-Zeev A, Oren M (1986) Specific interaction between the p53 cellular tumour antigen and major heat shock proteins. Nature 320:182–184

    CAS  PubMed  CrossRef  Google Scholar 

  33. Wiech M, Olszewski MB, Tracz-Gaszewska Z, Wawrzynow B, Zylicz M, Zylicz A (2012) Molecular mechanism of mutant p53 stabilization: the role of Hsp70 and MDM2. PLoS One 7:e51426–e51426

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  34. O’Callaghan-Sunol C, Gabai VL, Sherman MY (2007) Hsp27 modulates p53 signaling and suppresses cellular senescence. Cancer Res 67:11779–11788

    PubMed  CrossRef  CAS  Google Scholar 

  35. Bieging KT, Mello SS, Attardi LD (2014) Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer 14:359–370

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  36. Hoter A, Rizk S, Naim HY (2019) The multiple roles and therapeutic potential of molecular chaperones in prostate cancer. Cancers 11:1194–1194

    CAS  PubMed Central  CrossRef  Google Scholar 

  37. Hoter A, Naim HY (2019) Heat shock proteins and ovarian cancer: important roles and therapeutic opportunities. Cancers 11:1389–1389

    CAS  PubMed Central  CrossRef  Google Scholar 

  38. Xu L, Lin X, Zheng Y, Zhou H (2019) Silencing of heat shock protein 27 increases the radiosensitivity of non-small cell lung carcinoma cells. Mol Med Rep 20:613–621

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang C, Zhang Y, Guo K, Wang N, Jin H, Liu Y, Qin W (2016) Heat shock proteins in hepatocellular carcinoma: molecular mechanism and therapeutic potential. Int J Cancer 138:1824–1834

    CAS  PubMed  CrossRef  Google Scholar 

  40. Ghosh JC, Dohi T, Kang BH, Altieri DC (2008) Hsp60 regulation of tumor cell apoptosis. J Biol Chem 283:5188–5194

    CAS  PubMed  CrossRef  Google Scholar 

  41. Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T, Tailor P, Morimoto RI, Cohen GM, Green DR (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2:469–475

    CAS  PubMed  CrossRef  Google Scholar 

  42. Lanneau D, de Thonel A, Maurel S, Didelot C, Garrido C (2010) Apoptosis versus cell differentiation: role of heat shock proteins Hsp90, Hsp70 and Hsp27. Prion 1:53–60

    CrossRef  Google Scholar 

  43. Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Mitsiades N, Catley L, Tai YT, Hayashi T, Shringarpure R et al (2003) Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance. Blood 102:3379–3386

    CAS  PubMed  CrossRef  Google Scholar 

  44. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle (Georgetown, Tex) 5:2592–2601

    CAS  CrossRef  Google Scholar 

  45. Paul C, Simon S, Gibert B, Virot S, Manero F, Arrigo A-P (2010) Dynamic processes that reflect anti-apoptotic strategies set up by HspB1 (Hsp27). Exp Cell Res 316:1535–1552

    CAS  PubMed  CrossRef  Google Scholar 

  46. Arrigo AP, Gibert B (2012) HspB1 dynamic phospho-oligomeric structure dependent interactome as cancer therapeutic target. Curr Mol Med 12:1151–1163

    CAS  PubMed  CrossRef  Google Scholar 

  47. Toogun OA, Dezwaan DC, Freeman BC (2008) The Hsp90 molecular chaperone modulates multiple telomerase activities. Mol Cell Biol 28:457–467

    CAS  PubMed  CrossRef  Google Scholar 

  48. Cui X-B, Yu Z-Y, Wang W, Zheng Y-Q, Liu W, Li L-X (2012) Co-inhibition of Hsp70/Hsp90 synergistically sensitizes nasopharyngeal carcinoma cells to thermotherapy. Integr Cancer Ther 11:61–67

    CAS  PubMed  CrossRef  Google Scholar 

  49. Prince T, Ackerman A, Cavanaugh A, Schreiter B, Juengst B, Andolino C, Danella J, Chernin M, Williams H (2018) Dual targeting of Hsp70 does not induce the heat shock response and synergistically reduces cell viability in muscle invasive bladder cancer. Oncotarget 9:32702–32717

    PubMed  PubMed Central  CrossRef  Google Scholar 

  50. Calderwood SK, Gong J (2016) Heat shock proteins promote cancer: it’s a protection Racket. Trends Biochem Sci 41:311–323

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  51. Minet E, Mottet D, Michel G, Roland I, Raes M, Remacle J, Michiels C (1999) Hypoxia-induced activation of HIF-1: role of HIF-1alpha-Hsp90 interaction. FEBS Lett 460:251–256

    CAS  PubMed  CrossRef  Google Scholar 

  52. Joseph JV, Conroy S, Pavlov K, Sontakke P, Tomar T, Eggens-Meijer E, Balasubramaniyan V, Wagemakers M, den Dunnen WFA, Kruyt FAE (2015) Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α-ZEB1 axis. Cancer Lett 359:107–116

    CAS  PubMed  CrossRef  Google Scholar 

  53. Okui T, Shimo T, Hassan NMM, Fukazawa T, Kurio N, Takaoka M, Naomoto Y, Sasaki A (2011) Antitumor effect of novel Hsp90 inhibitor NVP-AUY922 against oral squamous cell carcinoma. Anticancer Res 31:1197–1204

    CAS  PubMed  Google Scholar 

  54. Tsutsumi S, Beebe K, Neckers L (2009) Impact of heat-shock protein 90 on cancer metastasis. Future Oncol (London, England) 5:679–688

    CAS  CrossRef  Google Scholar 

  55. Cano LQ, Lavery DN, Sin S, Spanjaard E, Brooke GN, Tilman JD, Abroaf A, Gaughan L, Robson CN, Heer R et al (2015) The co-chaperone p23 promotes prostate cancer motility and metastasis. Mol Oncol 9:295–308

    PubMed  CrossRef  CAS  Google Scholar 

  56. Miyajima N, Tsutsumi S, Sourbier C, Beebe K, Mollapour M, Rivas C, Yoshida S, Trepel JB, Huang Y, Tatokoro M et al (2013) The Hsp90 inhibitor ganetespib synergizes with the MET kinase inhibitor crizotinib in both crizotinib-sensitive and -resistant MET-driven tumor models. Cancer Res 73:7022–7033

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  57. Gibert B, Eckel B, Gonin V, Goldschneider D, Fombonne J, Deux B, Mehlen P, Arrigo AP, Clézardin P, Diaz-Latoud C (2012) Targeting heat shock protein 27 (HspB1) interferes with bone metastasis and tumour formation in vivo. Br J Cancer 107:63–70

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  58. Pavan S, Musiani D, Torchiaro E, Migliardi G, Gai M, Di Cunto F, Erriquez J, Olivero M, Di Renzo MF (2014) Hsp27 is required for invasion and metastasis triggered by hepatocyte growth factor. Int J Cancer 134:1289–1299

    CAS  PubMed  CrossRef  Google Scholar 

  59. Shiota M, Bishop JL, Nip KM, Zardan A, Takeuchi A, Cordonnier T, Beraldi E, Bazov J, Fazli L, Chi K et al (2013) Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer Res 73:3109–3119

    CAS  PubMed  CrossRef  Google Scholar 

  60. Pockley AG, Henderson B (2018) Extracellular cell stress (Heat shock) proteins—immune responses and disease: an overview. Philos Trans R Soc B Biol Sci 373:20160522

    CrossRef  CAS  Google Scholar 

  61. Santos TG, Martins VR, Hajj GNM (2017) Unconventional secretion of heat shock proteins in cancer. Int J Mol Sci 18:1–17

    Google Scholar 

  62. Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular Hsp70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    CAS  PubMed  CrossRef  Google Scholar 

  63. Dybdahl B, Wahba A, Lien E, Flo TH, Waage A, Qureshi N, Sellevold OFM, Espevik T, Sundan A (2002) Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 105:685–690

    CAS  PubMed  CrossRef  Google Scholar 

  64. Mortaz E, Redegeld FA, Nijkamp FP, Wong HR, Engels F (2006) Acetylsalicylic acid-induced release of Hsp70 from mast cells results in cell activation through TLR pathway. Exp Hematol 34:8–18

    CAS  PubMed  CrossRef  Google Scholar 

  65. Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H (2002) Hsp70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 277:15107–15112

    CAS  PubMed  CrossRef  Google Scholar 

  66. Bausero MA, Gastpar R, Multhoff G, Asea A (2005) Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J Immunol (Baltimore, Md: 1950) 175:2900–2912

    CAS  CrossRef  Google Scholar 

  67. Aneja R, Odoms K, Dunsmore K, Shanley TP, Wong HR (2006) Extracellular heat shock protein-70 induces endotoxin tolerance in THP-1 cells. J Immunol (Baltimore, Md: 1950) 177:7184–7192

    CAS  CrossRef  Google Scholar 

  68. Kovalchin JT, Wang R, Wagh MS, Azoulay J, Sanders M, Chandawarkar RY (2006) In vivo delivery of heat shock protein 70 accelerates wound healing by up-regulating macrophage-mediated phagocytosis. Wound Repair Regen 14:129–137

    PubMed  CrossRef  Google Scholar 

  69. Lv LH, Wan YL, Lin Y, Zhang W, Yang M, Li GN, Lin HM, Shang CZ, Chen YJ, Min J (2012) Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. J Biol Chem 287:15874–15885

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  70. Wang R, Kovalchin JT, Muhlenkamp P, Chandawarkar RY (2006) Exogenous heat shock protein 70 binds macrophage lipid raft microdomain and stimulates phagocytosis, processing, and MHC-II presentation of antigens. Blood 107:1636–1642

    CAS  PubMed  CrossRef  Google Scholar 

  71. Lee K-J, Kim YM, Kim DY, Jeoung D, Han K, Lee S-T, Lee Y-S, Park KH, Park JH, Kim DJ et al (2006) Release of heat shock protein 70 (Hsp70) and the effects of extracellular Hsp70 on matric metalloproteinase-9 expression in human monocytic U937 cells. Exp Mol Med 38:364–374

    CAS  PubMed  CrossRef  Google Scholar 

  72. Fong JJ, Sreedhara K, Deng L, Varki NM, Angata T, Liu Q, Nizet V, Varki A (2015) Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14. EMBO J 34:2775–2788

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  73. de la Mare JA, Jurgens T, Edkins AL (2017) Extracellular Hsp90 and TGFβ regulate adhesion, migration and anchorage independent growth in a paired colon cancer cell line model. BMC Cancer 17:1–16

    CrossRef  CAS  Google Scholar 

  74. Gehrmann M, Cervello M, Montalto G, Cappello F, Gulino A, Knape C, Specht HM, Multhoff G (2014a) Heat shock protein 70 serum levels differ significantly in patients with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Front Immunol 5:307–307

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  75. Gehrmann M, Specht HM, Bayer C, Brandstetter M, Chizzali B, Duma M, Breuninger S, Hube K, Lehnerer S, van Phi V et al (2014b) Hsp70–a biomarker for tumor detection and monitoring of outcome of radiation therapy in patients with squamous cell carcinoma of the head and neck. Radiat Oncol (London, England) 9:131–131

    CrossRef  Google Scholar 

  76. Zhao M, Ding JX, Zeng K, Zhao J, Shen F, Yin YX, Chen Q (2014) Heat shock protein 27: a potential biomarker of peritoneal metastasis in epithelial ovarian cancer? Tumour Biol 35:1051–1056

    PubMed  CrossRef  CAS  Google Scholar 

  77. Zimmermann M, Nickl S, Lambers C, Hacker S, Mitterbauer A, Hoetzenecker K, Rozsas A, Ostoros G, Laszlo V, Hofbauer H et al (2012) Discrimination of clinical stages in non-small cell lung cancer patients by serum Hsp27 and Hsp70: a multi-institutional case-control study. Clin Chim Acta 413:1115–1120

    CAS  PubMed  CrossRef  Google Scholar 

  78. Tas F, Bilgin E, Erturk K, Duranyildiz D (2017) Clinical significance of circulating serum cellular heat shock protein 90 (Hsp90) level in patients with cutaneous malignant melanoma. Asian Pac J Cancer Prev 18:599–601

    PubMed  PubMed Central  Google Scholar 

  79. Hoter A, El-Sabban ME, Naim HY (2018) The Hsp90 family: structure, regulation, function, and implications in health and disease. Int J Mol Sci 19:2560

    PubMed Central  CrossRef  CAS  Google Scholar 

  80. Shrestha L, Bolaender A, Patel HJ, Taldone T (2016) Heat Shock Protein (HSP) drug discovery and development: targeting heat shock proteins in disease. Curr Top Med Chem 16:2753–2764

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  81. Rajan A, Kelly RJ, Trepel JB, Kim YS, Alarcon SV, Kummar S, Gutierrez M, Crandon S, Zein WM, Jain L et al (2011) A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas. Clin Cancer Res 17:6831–6839

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  82. Menezes DL, Taverna P, Jensen MR, Abrams T, Stuart D, Yu GK, Duhl D, Machajewski T, Sellers WR, Pryer NK et al (2012) The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo. Mol Cancer Ther 11:730–739

    CAS  PubMed  CrossRef  Google Scholar 

  83. Zhang Y, Dayalan Naidu S, Samarasinghe K, Van Hecke GC, Pheely A, Boronina TN, Cole RN, Benjamin IJ, Cole PA, Ahn YH et al (2014) Sulphoxythiocarbamates modify cysteine residues in Hsp90 causing degradation of client proteins and inhibition of cancer cell proliferation. Br J Cancer 110:71–82

    CAS  PubMed  CrossRef  Google Scholar 

  84. Terracciano S, Russo A, Chini MG, Vaccaro MC, Potenza M, Vassallo A, Riccio R, Bifulco G, Bruno I (2018) Discovery of new molecular entities able to strongly interfere with Hsp90 C-terminal domain. Sci Rep 8:1709–1709

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  85. Ochiana SO, Taldone T, Chiosis G (2014) In: Houry WA (ed) Designing drugs against Hsp90 for cancer therapy. Springer New York, New York, pp 151–183

    Google Scholar 

  86. Patel HJ, Modi S, Chiosis G, Taldone T (2011) Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment. Expert Opin Drug Discovery 6:559–587

    CAS  CrossRef  Google Scholar 

  87. Soga S, Shiotsu Y, Akinaga S, Sharma SV (2003) Development of radicicol analogues. Curr Cancer Drug Targets 3:359–369

    CAS  PubMed  CrossRef  Google Scholar 

  88. Supko JG, Hickman RL, Grever MR, Malspeis L (1995) Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol 36:305–315

    CAS  PubMed  CrossRef  Google Scholar 

  89. Banerji U, O’Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y, Simmons L, Maloney A, Raynaud F, Campbell M et al (2005) Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23:4152–4161

    CAS  PubMed  CrossRef  Google Scholar 

  90. Mellatyar H, Talaei S, Pilehvar-Soltanahmadi Y, Barzegar A, Akbarzadeh A, Shahabi A, Barekati-Mowahed M, Zarghami N (2018) Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: overview and current state of the art. Biomed Pharmacother Biomed Pharmacotherapie 102:608–617

    CAS  CrossRef  Google Scholar 

  91. Marcu MG, Chadli A, Bouhouche I, Catelli M, Neckers LM (2000) The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. J Biol Chem 275:37181–37186

    CAS  PubMed  CrossRef  Google Scholar 

  92. Chadli A, Felts SJ, Wang Q, Sullivan WP, Botuyan MV, Fauq A, Ramirez-Alvarado M, Mer G (2010) Celastrol inhibits Hsp90 chaperoning of steroid receptors by inducing fibrillization of the co-chaperone p23. J Biol Chem 285:4224–4231

    CAS  PubMed  CrossRef  Google Scholar 

  93. Smith JR, Clarke PA, de Billy E, Workman P (2009) Silencing the cochaperone CDC37 destabilizes kinase clients and sensitizes cancer cells to Hsp90 inhibitors. Oncogene 28:157–169

    CAS  PubMed  CrossRef  Google Scholar 

  94. Smith JR, Workman P (2009) Targeting CDC37: an alternative, kinase-directed strategy for disruption of oncogenic chaperoning. Cell Cycle (Georgetown, Tex) 8:362–372

    CAS  CrossRef  Google Scholar 

  95. Dutta Gupta S, Bommaka MK, Banerjee A (2019) Inhibiting protein-protein interactions of Hsp90 as a novel approach for targeting cancer. Eur J Med Chem 178:48–63

    CAS  PubMed  CrossRef  Google Scholar 

  96. Kumar S, Stokes J, Singh UP, Scissum Gunn K, Acharya A, Manne U, Mishra M (2016) Targeting Hsp70: a possible therapy for cancer. Cancer Lett 374:156–166

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  97. Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of Hsp70: a challenging anti-cancer strategy. Cancer Lett 325:117–124

    CAS  PubMed  CrossRef  Google Scholar 

  98. Powers MV, Jones K, Barillari C, Westwood I, van Montfort RLM, Workman P (2010) Targeting Hsp70: the second potentially druggable heat shock protein and molecular chaperone? Cell Cycle (Georgetown, Tex) 9:1542–1550

    CAS  CrossRef  Google Scholar 

  99. Britten CD, Rowinsky EK, Baker SD, Weiss GR, Smith L, Stephenson J, Rothenberg M, Smetzer L, Cramer J, Collins W et al (2000) A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077. Clin Cancer Res 6:42–49

    CAS  PubMed  Google Scholar 

  100. Kaiser M, Kühnl A, Reins J, Fischer S, Ortiz-Tanchez J, Schlee C, Mochmann LH, Heesch S, Benlasfer O, Hofmann WK et al (2011) Antileukemic activity of the Hsp70 inhibitor pifithrin-μ in acute leukemia. Blood Cancer J 1:e28–e28

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  101. Nadeau K, Nadler SG, Saulnier M, Tepper MA, Walsh CT (1994) Quantitation of the interaction of the immunosuppressant deoxyspergualin and analogs with Hsc70 and Hsp90. Biochemistry 33:2561–2567

    CAS  PubMed  CrossRef  Google Scholar 

  102. Rodina A, Vilenchik M, Moulick K, Aguirre J, Kim J, Chiang A, Litz J, Clement CC, Kang Y, She Y et al (2007) Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat Chem Biol 3:498–507

    CAS  PubMed  CrossRef  Google Scholar 

  103. Braunstein MJ, Scott SS, Scott CM, Behrman S, Walter P, Wipf P, Coplan JD, Chrico W, Joseph D, Brodsky JL et al (2011) Antimyeloma effects of the heat shock protein 70 molecular chaperone inhibitor MAL3-101. J Oncol 2011:232037–232037

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  104. Whetstone H, Lingwood C (2003) 3′sulfogalactolipid binding specifically inhibits Hsp70 ATPase activity in vitro. Biochemistry 42:1611–1617

    CAS  PubMed  CrossRef  Google Scholar 

  105. Massey AJ, Williamson DS, Browne H, Murray JB, Dokurno P, Shaw T, Macias AT, Daniels Z, Geoffroy S, Dopson M et al (2010) A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 66:535–545

    CAS  PubMed  CrossRef  Google Scholar 

  106. Chatterjee M, Andrulis M, Stühmer T, Müller E, Hofmann C, Steinbrunn T, Heimberger T, Schraud H, Kressmann S, Einsele H et al (2013) The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma. Haematologica 98:1132–1141

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  107. Rérole A-L, Gobbo J, De Thonel A, Schmitt E, Pais de Barros JP, Hammann A, Lanneau D, Fourmaux E, Demidov ON, Deminov O et al (2011) Peptides and aptamers targeting Hsp70: a novel approach for anticancer chemotherapy. Cancer Res 71:484–495

    PubMed  CrossRef  CAS  Google Scholar 

  108. Stangl S, Gehrmann M, Riegger J, Kuhs K, Riederer I, Sievert W, Hube K, Mocikat R, Dressel R, Kremmer E et al (2011) Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody. Proc Natl Acad Sci U S A 108:733–738

    CAS  PubMed  CrossRef  Google Scholar 

  109. Meng Q, Li BX, Xiao X (2018) Toward developing chemical modulators of Hsp60 as potential therapeutics. Front Mol Biosci 5:35–35

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  110. Itoh H, Komatsuda A, Wakui H, Miura AB, Tashima Y (1999) Mammalian Hsp60 is a major target for an immunosuppressant mizoribine. J Biol Chem 274:35147–35151

    CAS  PubMed  CrossRef  Google Scholar 

  111. Tanabe M, Ishida R, Izuhara F, Komatsuda A, Wakui H, Sawada K, Otaka M, Nakamura N, Itoh H (2012) The ATPase activity of molecular chaperone Hsp60 is inhibited by immunosuppressant mizoribine. Am J Mol Biol 2:93–102

    CAS  CrossRef  Google Scholar 

  112. Nagumo Y, Kakeya H, Shoji M, Hayashi Y, Dohmae N, Osada H (2005) Epolactaene binds human Hsp60 Cys442 resulting in the inhibition of chaperone activity. Biochem J 387:835–840

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  113. Wiechmann K, Müller H, König S, Wielsch N, Svatoš A, Jauch J, Werz O (2017) Mitochondrial chaperonin Hsp60 Is the apoptosis-related target for myrtucommulone. Cell Chem Biol 24:614–623.e616

    CAS  PubMed  CrossRef  Google Scholar 

  114. Qian-Cutrone J, Huang S, Shu Y-Z, Vyas D, Fairchild C, Menendez A, Krampitz K, Dalterio R, Klohr SE, Gao Q (2002) Stephacidin A and B: two structurally novel, selective inhibitors of the testosterone-dependent prostate LNCaP cells. J Am Chem Soc 124:14556–14557

    CAS  PubMed  CrossRef  Google Scholar 

  115. Wulff JE, Herzon SB, Siegrist R, Myers AG (2007) Evidence for the rapid conversion of stephacidin B into the electrophilic monomer avrainvillamide in cell culture. J Am Chem Soc 129:4898–4899

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  116. Fenical WJPR, Cheng XC (2000) Avrainvillamide, a cytotoxic marine natural product, and derivatives there of US patent

    Google Scholar 

  117. Ban HS, Shimizu K, Minegishi H, Nakamura H (2010) Identification of Hsp60 as a primary target of o-carboranylphenoxyacetanilide, an HIF-1alpha inhibitor. J Am Chem Soc 132:11870–11871

    CAS  PubMed  CrossRef  Google Scholar 

  118. Hu D, Liu Y, Lai Y-T, Tong K-C, Fung Y-M, Lok C-N, Che C-M (2016) Anticancer Gold(III) porphyrins target mitochondrial chaperone Hsp60. Angew Chem Int Ed Engl 55:1387–1391

    CAS  PubMed  CrossRef  Google Scholar 

  119. Lease N, Vasilevski V, Carreira M, de Almeida A, Sanaú M, Hirva P, Casini A, Contel M (2013) Potential anticancer heterometallic Fe-Au and Fe-Pd agents: initial mechanistic insights. J Med Chem 56:5806–5818

    CAS  PubMed  CrossRef  Google Scholar 

  120. Teo RD, Gray HB, Lim P, Termini J, Domeshek E, Gross Z (2014) A cytotoxic and cytostatic gold(III) corrole. Chem Commun (Camb) 50:13789–13792

    CAS  CrossRef  Google Scholar 

  121. Choi S-K, Kam H, Kim K-Y, Park SI, Lee Y-S (2019) Targeting heat shock protein 27 in cancer: a druggable target for cancer treatment? Cancers 11:1195–1195

    CAS  PubMed Central  CrossRef  Google Scholar 

  122. Murakami A, Ashida H, Terao J (2008) Multitargeted cancer prevention by quercetin. Cancer Lett 269:315–325

    CAS  PubMed  CrossRef  Google Scholar 

  123. Nagai N, Nakai A, Nagata K (1995) Quercetin suppresses heat shock response by down regulation of HSF1. Biochem Biophys Res Commun 208:1099–1105

    CAS  PubMed  CrossRef  Google Scholar 

  124. Heinrich J-C, Tuukkanen A, Schroeder M, Fahrig T, Fahrig R (2011) RP101 (brivudine) binds to heat shock protein Hsp27 (HSPB1) and enhances survival in animals and pancreatic cancer patients. J Cancer Res Clin Oncol 137:1349–1361

    PubMed  CrossRef  Google Scholar 

  125. Heinrich JC, Donakonda S, Haupt VJ, Lennig P (2016) New Hsp27 inhibitors efficiently down-regulate resistance development in cancer cells. Oncotarget 7:68156–68169

    PubMed  PubMed Central  CrossRef  Google Scholar 

  126. Choi B, Choi S-K, Park YN, Kwak S-Y, Lee HJ, Kwon Y, Na Y, Lee Y-S (2017) Sensitization of lung cancer cells by altered dimerization of Hsp27. Oncotarget 8:105372–105382

    PubMed  PubMed Central  CrossRef  Google Scholar 

  127. Kumano M, Furukawa J, Shiota M, Zardan A, Zhang F, Beraldi E, Wiedmann RM, Fazli L, Zoubeidi A, Gleave ME (2012) Cotargeting stress-activated Hsp27 and autophagy as a combinatorial strategy to amplify endoplasmic reticular stress in prostate cancer. Mol Cancer Ther 11:1661–1671

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  128. Lelj-Garolla B, Kumano M, Beraldi E, Nappi L, Rocchi P, Ionescu DN, Fazli L, Zoubeidi A, Gleave ME (2015) Hsp27 Inhibition with OGX-427 sensitizes non-small cell lung cancer cells to erlotinib and chemotherapy. Mol Cancer Ther 14:1107–1116

    CAS  PubMed  CrossRef  Google Scholar 

  129. Seigneuric R, Gobbo J, Colas P, Garrido C (2011) Targeting cancer with peptide aptamers. Oncotarget 2:557–561

    PubMed  PubMed Central  CrossRef  Google Scholar 

  130. Hosokawa N, Hirayoshi K, Kudo H, Takechi H, Aoike A, Kawai K, Nagata K (1992) Inhibition of the activation of heat shock factor in vivo and in vitro by flavonoids. Mol Cell Biol 12:3490–3498

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Elattar TM, Virji AS (2000) The inhibitory effect of curcumin, genistein, quercetin and cisplatin on the growth of oral cancer cells in vitro. Anticancer Res 20:1733–1738

    CAS  PubMed  Google Scholar 

  132. Yoshida M, Sakai T, Hosokawa N, Marui N, Matsumoto K, Fujioka A, Nishino H, Aoike A (1990) The effect of quercetin on cell cycle progression and growth of human gastric cancer cells. FEBS Lett 260:10–13

    CAS  PubMed  CrossRef  Google Scholar 

  133. Borgo C, Vilardell J, Bosello-Travain V, Pinna LA, Venerando A, Salvi M (2018) Dependence of Hsp27 cellular level on protein kinase CK2 discloses novel therapeutic strategies. Biochim Biophys Acta Gen Subj 1862:2902–2910

    CAS  PubMed  CrossRef  Google Scholar 

  134. Russo M, Milito A, Spagnuolo C, Carbone V, Rosén A, Minasi P, Lauria F, Russo GL (2017) CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia. Oncotarget 8:42571–42587

    PubMed  PubMed Central  CrossRef  Google Scholar 

  135. McConnell JR, McAlpine SR (2013) Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. Bioorg Med Chem Lett 23:1923–1928

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  136. Hadchity E, Aloy M-T, Paulin C, Armandy E, Watkin E, Rousson R, Gleave M, Chapet O, Rodriguez-Lafrasse C (2009) Heat shock protein 27 as a new therapeutic target for radiation sensitization of head and neck squamous cell carcinoma. Mol Ther 17:1387–1394

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  137. Hossen S, Hossain MK, Basher MK, Mia MNH, Rahman MT, Uddin MJ (2019) Smart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: a review. J Adv Res 15:1–18

    CAS  PubMed  CrossRef  Google Scholar 

  138. Egusquiaguirre SP, Igartua M, Hernández RM, Pedraz JL (2012) Nanoparticle delivery systems for cancer therapy: advances in clinical and preclinical research. Clin Transl Oncol 14:83–93

    CAS  PubMed  CrossRef  Google Scholar 

  139. Bhatia S (2016) Nanoparticles types, classification, characterization, fabrication methods and drug delivery applications. Springer International Publishing, Cham, pp 33–93

    Google Scholar 

  140. Dong S (2008) Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy. Int J Nanomedicine 3(3):311

    CrossRef  Google Scholar 

  141. Dulińska-Litewka J, Łazarczyk A, Hałubiec P, Szafrański O, Karnas K, Karewicz A (2019) Superparamagnetic iron oxide nanoparticles—current and prospective medical applications. Materials 12:617

    PubMed Central  CrossRef  CAS  Google Scholar 

  142. Wahajuddin, Arora S (2012) Superparamagnetic iron oxide nanoparticles: magnetic nanoplatforms as drug carriers. Int J Nanomedicine 7:3445

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  143. Fu C, Ravindra NM (2012) Magnetic iron oxide nanoparticles: synthesis and applications. Bioinspired Biomimetic Nanobiomater 1:229–244

    CAS  CrossRef  Google Scholar 

  144. Mahmoudi M, Sant S, Wang B, Laurent S, Sen T (2011) Superparamagnetic iron oxide nanoparticles (SPIONs): Development, surface modification and applications in chemotherapy. Adv Drug Deliv Rev 63:24–46

    CAS  PubMed  CrossRef  Google Scholar 

  145. Patil U, Adireddy S, Jaiswal A, Mandava S, Lee B, Chrisey D (2015) In vitro/in vivo toxicity evaluation and quantification of iron oxide nanoparticles. Int J Mol Sci 16:24417–24450

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  146. Ali A, Zafar H, Zia M, ul Haq I, Phull AR, Ali JS, Hussain A (2016) Synthesis, characterization, applications, and challenges of iron oxide nanoparticles. Nanotechnol Sci Appl 9:49–67

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  147. Arias L, Pessan J, Vieira A, Lima T, Delbem A, Monteiro D (2018) Iron oxide nanoparticles for biomedical applications: a perspective on synthesis, drugs, antimicrobial activity, and toxicity. Antibiotics 7:46

    PubMed Central  CrossRef  CAS  Google Scholar 

  148. Baillot M, Hemery G, Sandre O, Schmitt V, Backov R (2017) Thermomagnetically responsive γ-Fe2O3@Wax@SiO2 sub-micrometer capsules. Part Part Syst Charact 34:1700063

    CrossRef  CAS  Google Scholar 

  149. Li W, Yu H, Ding D, Chen Z, Wang Y, Wang S, Li X, Keidar M, Zhang W (2019) Cold atmospheric plasma and iron oxide-based magnetic nanoparticles for synergetic lung cancer therapy. Free Radic Biol Med 130:71–81

    CAS  PubMed  CrossRef  Google Scholar 

  150. Kumar P, Agnihotri S, Roy I (2018) Preparation and characterization of superparamagnetic iron oxide nanoparticles for magnetically guided drug delivery. Int J Nanomedicine 13:43–46

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  151. Revia RA, Zhang M (2016) Magnetite nanoparticles for cancer diagnosis, treatment, and treatment monitoring: recent advances. Mater Today 19:157–168

    CAS  CrossRef  Google Scholar 

  152. Ito A, Matsuoka F, Honda H, Kobayashi T (2003) Heat shock protein 70 gene therapy combined with hyperthermia using magnetic nanoparticles. Cancer Gene Ther 10:918–925

    CAS  PubMed  CrossRef  Google Scholar 

  153. Ito A, Saito H, Mitobe K, Minamiya Y, Takahashi N, Maruyama K, Motoyama S, Katayose Y, Ogawa J-I (2009) Inhibition of heat shock protein 90 sensitizes melanoma cells to thermosensitive ferromagnetic particle-mediated hyperthermia with low Curie temperature. Cancer Sci 100:558–564

    CAS  PubMed  CrossRef  Google Scholar 

  154. Vriend LEM, Tempel NVD, Oei AL, L’Acosta M, Pieterson FJ, Franken NAP, Kanaar R, Krawczyk PM (2017) Boosting the effects of hyperthermia-based anticancer treatments by Hsp90 inhibition. Oncotarget 8:97490–97503

    PubMed  PubMed Central  CrossRef  Google Scholar 

  155. Court KA, Hatakeyama H, Wu SY, Lingegowda MS, Rodríguez-Aguayo C, López-Berestein G, Ju-Seog L, Rinaldi C, Juan EJ, Sood AK et al (2017) Hsp70 inhibition synergistically enhances the effects of magnetic fluid hyperthermia in ovarian cancer. Mol Cancer Ther 16:966–976

    CAS  PubMed  CrossRef  Google Scholar 

  156. Rosman R, Saifullah B, Maniam S, Dorniani D, Hussein M, Fakurazi S (2018) Improved anticancer effect of magnetite nanocomposite formulation of GALLIC acid (Fe3O4-PEG-GA) against lung, breast and colon cancer cells. Nano 8:83

    Google Scholar 

  157. Wu VM, Huynh E, Tang S, Uskoković V (2019) Brain and bone cancer targeting by a ferrofluid composed of superparamagnetic iron-oxide/silica/carbon nanoparticles (earthicles). Acta Biomater 88:422–447

    CAS  PubMed  CrossRef  Google Scholar 

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Acknowledgements

We would like to thank the Deanship of Scientific Research and RSSU at King Saud University for their technical support.

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All authors declare they have no conflict of interest.

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Ethical Approval for Studies Involving Animals

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Hoter, A., Alsantely, A.O., Alsharaeh, E., Kulik, G., Saadeldin, I.M. (2020). Combined Thermotherapy and Heat Shock Protein Modulation for Tumor Treatment. In: Asea, A.A.A., Kaur, P. (eds) Heat Shock Proteins in Human Diseases. Heat Shock Proteins, vol 21. Springer, Cham. https://doi.org/10.1007/7515_2020_13

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