Heat Shock Proteins (HSPs): A Novel Target for Cancer Metastasis Prevention

Author(s): Vinayak Narayanankutty, Arunaksharan Narayanankutty*, Anusree Nair.

Journal Name: Current Drug Targets

Volume 20 , Issue 7 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Background: Heat shock proteins (HSPs) are predominant molecular chaperones which are actively involved in the protein folding; which is essential in protecting the structure and functioning of proteins during various stress conditions. Though HSPs have important physiological roles, they have been well known for their roles in various pathogenic conditions such as carcinogenesis; however, limited literature has consolidated its potential as an anti-metastatic drug target.

Objectives: The present review outlines the role of different HSPs on cancer progression and metastasis; possible role of HSP inhibitors as anti-neoplastic agents is also discussed.

Methods: The data were collected from PubMed/Medline and other reputed journal databases. The literature that was too old and had no significant role to the review was then omitted.

Results: Despite their strong physiological functions, HSPs are considered as good markers for cancer prognosis and diagnosis. They have control over survival, proliferation and progression events of cancer including drug resistance, metastasis, and angiogenesis. Since, neoplastic cells are more dependent on HSPs for survival and proliferation, the selectivity and specificity of HSP-targeted cancer drugs remain high. This has made various HSPs potential clinical and experimental targets for cancer prevention. An array of HSP inhibitors has been in trials and many others are in experimental conditions as anticancer and anti-metastatic agents. Several natural products are also being investigated for their efficacy for anticancer and anti-metastatic agents by modulating HSPs.

Conclusion: Apart from their role as an anticancer drug target, HSPs have shown to be promising targets for the prevention of cancer progression. Extensive studies are required for the use of these molecules as anti-metastatic agents. Further studies in this line may yield specific and effective antimetastatic agents.

Keywords: Heat shock proteins, cancer, metastasis, epithelial to mesenchymal transition, HSP inhibitors, natural products.

Liu Y, Zhang X. Heat shock protein reports on proteome stress. Biotechnol J 2018; 13: 5.
Lechner P, Buck D, Sick L, Hemmer B, Multhoff G. Serum heat shock protein 70 levels as a biomarker for inflammatory processes in multiple sclerosis. Mult Scler J Exp Transl Clin 2018; 4: 2055217318767192.
Edkins AL, Price JT, Pockley AG, Blatch GL. Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective. Philos Trans R Soc Lond B Biol Sci 2018; 373: 20160521.
Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES. Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2000; 2: 476-83.
Ravagnan L, Gurbuxani S, Susin SA, et al. Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 2001; 3: 839-43.
Boudesco C, Rattier T, Garrido C, Jego G. Do not stress, just differentiate: role of stress proteins in hematopoiesis. Cell Death Dis 2015; 6: e1628.
Jagadish N, Agarwal S, Gupta N, et al. Heat shock protein 70-2 (HSP70-2) overexpression in breast cancer. J Exp Clin Cancer Res 2016; 35: 150.
Wang J, Cui S, Zhang X, Wu Y, Tang H. High Expression of heat shock protein 90 is associated with tumor aggressiveness and poor prognosis in patients with advanced gastric cancer. PLoS One 2013; 8: e62876.
Zagouri F, Bournakis E, Koutsoukos K, Papadimitriou CA. Heat shock protein 90 (hsp90) expression and breast cancer. Pharmaceuticals 2012; 5: 1008-20.
Li X-S, Xu Q, Fu X-Y, Luo W-S. Heat Shock protein 60 overexpression is associated with the progression and prognosis in gastric cancer. PLoS One 2014; 9: e107507.
Calderwood SK, Gong J. Heat shock proteins promote cancer: it’s a protection racket. Trends Biochem Sci 2016; 41: 311-23.
Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat shock proteins and cancer. Trends Pharmacol Sci 2017; 38: 226-56.
Ge H, Yan Y, Guo L, Tian F, Wu D. Prognostic role of HSPs in human gastrointestinal cancer: a systematic review and meta-analysis. OncoTargets Ther 2018; 11: 351-9.
Zoubeidi A, Gleave M. Small heat shock proteins in cancer therapy and prognosis. Int J Biochem Cell Biol 2012; 44: 1646-56.
Acunzo J, Andrieu C, Baylot V, So A, Rocchi P. Hsp27 as a therapeutic target in cancers. Curr Drug Targets 2014; 15: 423-31.
Vahid S, Thaper D, Gibson KF, Bishop JL, Zoubeidi A. Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer. Sci Rep 2016; 24(6): 31842.
Cappello F, Zummo G. HSP60 expression during carcinogenesis: a molecular “Proteus” of carcinogenesis? Cell Stress Chaperones 2005; 10: 263-4.
Meng Q, Li BX, Xiao X. Toward developing chemical modulators of hsp60 as potential therapeutics. Front Mol Biosci 2018; 5: 35.
Barrott JJ, Haystead TAJ. Hsp90, an unlikely ally in the war on cancer. FEBS J 2013; 280(6): 1381-96.
Miyata Y, Nakamoto H, Neckers L. The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des 2013; 19: 347-65.
Ghosh JC, Dohi T, Kang BH, Altieri DC. Hsp60 Regulation of Tumor Cell Apoptosis. J Biol Chem 2008; 283: 5188-94.
Kumar S, Stokes J III, Singh UP, et al. Targeting Hsp70: A possible therapy for cancer. Cancer Lett 2016; 374: 156-66.
Murphy ME. The HSP70 family and cancer. Carcinogenesis 2013; 34: 1181-8.
Tsutsumi S, Beebe K, Neckers L. Impact of heat-shock protein 90 on cancer metastasis. Future oncology (London, England) 2009; 5: 679-88.
Koga F, Kihara K, Neckers L. Inhibition of cancer invasion and metastasis by targeting the molecular chaperone heat-shock protein 90. Anticancer Res 2009; 29: 797-807.
Tsen F, Bhatia A, O’Brien K, et al. Extracellular Heat shock protein 90 signals through subdomain ii and the npvy motif of lrp-1 receptor to akt1 and akt2: a circuit essential for promoting skin cell migration in vitro and wound healing in vivo. Mol Cell Biol 2013; 33: 4947-59.
Stellas D, El Hamidieh A, Patsavoudi E. Monoclonal antibody 4C5 prevents activation of MMP2 and MMP9 by disrupting their interaction with extracellular HSP90 and inhibits formation of metastatic breast cancer cell deposits. BMC Cell Biol 2010; 11: 1471-2121.
Yang Y, Rao R, Shen J, et al. Role of acetylation and extracellular location of heat shock protein 90alpha in tumor cell invasion. Cancer Res 2008; 68: 4833-42.
Gao F, Hu X, Xie X, Liu X, Wang J. Heat shock protein 90 stimulates rat mesenchymal stem cell migration via PI3K/Akt and ERK1/2 pathways. Cell Biochem Biophys 2015; 71: 481-9.
Chen W-S, Chen C-C, Chen L-L, Lee C-C, Huang T-S. Secreted Heat Shock Protein 90α (HSP90α) Induces Nuclear Factor-κB-mediated TCF12 Protein Expression to Down-regulate E-cadherin and to Enhance Colorectal Cancer Cell Migration and Invasion. J Biol Chem 2013; 288: 9001-10.
Hunter MC, O’Hagan KL, Kenyon A, et al. Hsp90 binds directly to fibronectin (fn) and inhibition reduces the extracellular fibronectin matrix in breast cancer cells. PLoS One 2014; 9: e86842.
Liu X, Yan Z, Huang L, et al. Cell surface heat shock protein 90 modulates prostate cancer cell adhesion and invasion through the integrin-beta1/focal adhesion kinase/c-Src signaling pathway. Oncol Rep 2011; 25: 1343-51.
Liu XG, Guo Y, Yan ZQ, et al. FAK/c-Src signaling pathway mediates the expression of cell surface HSP90 in cultured human prostate cancer cells and its association with their invasive capability. Zhonghua Zhong Liu Za Zhi 2011; 33: 340-4.
Nagaraju GP, Long TE, Park W, et al. Heat shock protein 90 promotes epithelial to mesenchymal transition, invasion, and migration in colorectal cancer. Mol Carcinog 2015; 54: 1147-58.
Hance MW, Dole K, Gopal U, et al. Secreted Hsp90 is a novel regulator of the epithelial to mesenchymal transition (EMT) in prostate cancer. J Biol Chem 2012; 287: 37732-44.
Sims JD, McCready J, Jay DG. Extracellular heat shock protein (hsp)70 and hsp90α assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion. PLoS One 2011; 6: e18848.
Park SL, Chung T-W, Kim S, et al. HSP70-1 is required for interleukin-5-induced angiogenic responses through eNOS pathway. Scientific Reports 2017; 7: 44687.
Kim TK, Na HJ, Lee WR, Jeoung MH, Lee S. Heat shock protein 70-1A is a novel angiogenic regulator. Biochem Biophys Res Commun 2016; 469: 222-8.
Kang Q, Cai JB, Dong RZ, et al. Mortalin promotes cell proliferation and epithelial mesenchymal transition of intrahepatic cholangiocarcinoma cells in vitro. J Clin Pathol 2017; 70: 677-83.
Yun C-O, Bhargava P, Na Y, et al. Relevance of mortalin to cancer cell stemness and cancer therapy. Scientific Reports 2017; 7: 42016.
Dhanani KCH, Samson WJ, Edkins AL. Fibronectin is a stress responsive gene regulated by HSF1 in response to geldanamycin. Scientific Reports 2017; 7: 17617.
Xi C, Hu Y, Buckhaults P, Moskophidis D, Mivechi NF. Heat shock factor hsf1 cooperates with erbb2 (her2/neu) protein to promote mammary tumorigenesis and metastasis. J Biol Chem 2012; 287: 35646-57.
Schulz R, Streller F, Scheel AH, et al. HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer. Cell Death &Amp. Disease 2014; 5: e980.
Rajesh Y, Biswas A, Mandal M. Glioma progression through the prism of heat shock protein mediated extracellular matrix remodeling and epithelial to mesenchymal transition. Exp Cell Res 2017; 359: 299-311.
Guo K, Kang NX, Li Y, et al. Regulation of HSP27 on NF-κB pathway activation may be involved in metastatic hepatocellular carcinoma cells apoptosis. BMC Cancer 2009; 9: 100.
Pavan S, Musiani D, Torchiaro E, et al. HSP27 is required for invasion and metastasis triggered by hepatocyte growth factor. Int J Cancer 2014; 134: 1289-99.
Schuster C, Akslen LA, Straume O. Expression of heat shock protein 27 in melanoma metastases is associated with overall response to bevacizumab monotherapy: analyses of predictive markers in a clinical phase ii study. PLoS One 2016; 11: e0155242.
Shiota M, Bishop JL, Nip KM, et al. Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer Res 2013; 73: 3109-19.
Voll EA, Ogden IM, Pavese JM, et al. Heat shock protein 27 regulates human prostate cancer cell motility and metastatic progression. Oncotarget 2014; 5: 2648-63.
Zhang Y, Tao X, Jin G, et al. A Targetable molecular chaperone hsp27 confers aggressiveness in hepatocellular carcinoma. Theranostics 2016; 6: 558-70.
Ghosh S, Shinogle HE, Galeva NA, Dobrowsky RT, Blagg BSJ. Endoplasmic reticulum-resident heat shock protein 90 (hsp90) isoform glucose-regulated protein 94 (grp94) regulates cell polarity and cancer cell migration by affecting intracellular transport. J Biol Chem 2016; 291: 8309-23.
Li J, Buchner J. Structure, function and regulation of the hsp90 machinery. Biomed J 2013; 36: 106-17.
Becker B, Multhoff G, Farkas B, et al. Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Exp Dermatol 2004; 13: 27-32.
Ethun CG, Postlewait LM, Lopez-Aguiar AG, et al. HSP90 expression and early recurrence in gastroenteropancreatic neuroendocrine tumors: Potential for novel therapeutic targets. J Clin Oncol 2017; 35: 235-5.
Armstrong HK, Gillis JL, Johnson IRD, et al. Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion. Scientific Reports 2018; 8: 2090.
Eustace BK, Sakurai T, Stewart JK, et al. Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat Cell Biol 2004; 6: 507-14.
Sidera K, Gaitanou M, Stellas D, Matsas R, Patsavoudi E. A critical role for HSP90 in cancer cell invasion involves interaction with the extracellular domain of HER-2. J Biol Chem 2008; 283: 2031-41.
Li CL, Yang D, Cao X, et al. Fibronectin induces epithelial-mesenchymal transition in human breast cancer MCF-7 cells via activation of calpain. Oncol Lett 2017; 13: 3889-95.
Teng Y, Ngoka L, Mei Y, Lesoon L, Cowell JK. HSP90 and HSP70 proteins are essential for stabilization and activation of wasf3 metastasis-promoting protein. J Biol Chem 2012; 287: 10051-9.
Ory B, Baud’huin M, Verrecchia F, Royer BB, Quillard T, Amiaud J, et al. Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression. Clin Cancer Res 2016; 22: 2520-33.
Wang Y, Lin F, Zhu X, et al. Distinct roles of intracellular heat shock protein 70 in maintaining gastrointestinal homeostasis. Am J Physiol Gastrointest Liver Physiol 2018; 314: G164-78.
Edkins AL, Price JT, Pockley AG, Blatch GL. Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective. Philos Trans R Soc Lond B Biol Sci 2018; 373: 20160521.
Shevtsov M, Huile G, Multhoff G. Membrane heat shock protein 70: a theranostic target for cancer therapy. Philosophical Transactions of the Royal Society B. Biol Sci 2018; 373: 20160526.
Teng Y, Ngoka L, Mei Y, Lesoon L, Cowell JK. HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein. J Biol Chem 2012; 287: 10051-9.
Na Y, Kaul SC, Ryu J, et al. Stress chaperone mortalin contributes to epithelial-to-mesenchymal transition and cancer metastasis. Cancer Res 2016; 76: 2754-65.
Wu P-K, Hong S-K, Veeranki S, et al. A mortalin/hspa9-mediated switch in tumor-suppressive signaling of raf/mek/extracellular signal-regulated kinase. Mol Cell Biol 2013; 33: 4051-67.
Su T, Liao J, Dai Z, et al. Stress-induced phosphoprotein 1 mediates hepatocellular carcinoma metastasis after insufficient radiofrequency ablation. Oncogene 2018; 37: 3514-27.
Fonseca AC, Romao L, Amaral RF, et al. Microglial stress inducible protein 1 promotes proliferation and migration in human glioblastoma cells. Neurosci 2012; 200: 130-41.
Carvalho da Fonseca AC, Wang H, Fan H, et al. Increased expression of stress inducible protein 1 in glioma-associated microglia/macrophages. J Neuroimmunol 2014; 274: 71-7.
Kubota H, Yamamoto S, Itoh E, et al. Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma. Cell Stress Chaperones 2010; 15: 1003-11.
Zhai E, Liang W, Lin Y, et al. HSP70/HSP90-organizing protein contributes to gastric cancer progression in an autocrine fashion and predicts poor survival in gastric cancer. Cell Physiol Biochem 2018; 47: 879-92.
Walsh N, Larkin A, Swan N, et al. RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation. Cancer Lett 2011; 306: 180-9.
Patwardhan CA, Fauq A, Peterson LB, et al. Gedunin Inactivates the co-chaperone p23 protein causing cancer cell death by apoptosis. J Biol Chem 2013; 288: 7313-25.
Lanneau D, Brunet M, Frisan E, et al. Heat shock proteins: essential proteins for apoptosis regulation. J Cell Mol Med 2008; 12: 743-61.
Kennedy D, Jager R, Mosser DD, Samali A. Regulation of apoptosis by heat shock proteins. IUBMB Life 2014; 66: 327-38.
Tang H, Chen Y, Liu X, et al. Downregulation of HSP60 disrupts mitochondrial proteostasis to promote tumorigenesis and progression in clear cell renal cell carcinoma. Oncotarget 2016; 7: 38822-34.
Zhang J, Zhou X, Chang H, et al. Hsp60 exerts a tumor suppressor function by inducing cell differentiation and inhibiting invasion in hepatocellular carcinoma. Oncotarget 2016; 7: 68976-89.
Tsai YP, Yang MH, Huang CH, et al. Interaction between HSP60 and beta-catenin promotes metastasis. Carcinogenesis 2009; 30: 1049-57.
Tang H, Li J, Liu X, et al. Down-regulation of HSP60 suppresses the proliferation of glioblastoma cells via the ROS/AMPK/mTOR Pathway. Sci Rep 2016; 6.
Yan F-Q, Wang J-Q, Tsai Y-P, Wu K-J. HSP60 overexpression increases the protein levels of the p110α subunit of phosphoinositide 3-kinase and c-Myc. Clin Exp Pharmacol Physiol 2015; 42: 1092-7.
Hjerpe E, Egyhazi S, Carlson J, et al. HSP60 predicts survival in advanced serous ovarian cancer. Int J Gynecol Cancer 2013; 23: 448-55.
Stope MB, Koensgen D, Burchardt M, et al. Jump in the fire--heat shock proteins and their impact on ovarian cancer therapy. Crit Rev Oncol Hematol 2016; 97: 152-6.
Bodzek P, Partyka R, Damasiewicz-Bodzek A. Antibodies against Hsp60 and Hsp65 in the sera of women with ovarian cancer. J Ovarian Res 2014; 7: 30.
Chun JN, Choi B, Lee KW, et al. Cytosolic hsp60 is involved in the nf-κb-dependent survival of cancer cells via ikk regulation. PLoS One 2010; 5: e9422.
Fletcher NM, Memaj I, Diamond MP, Morris RT, Saed GM. Heat shock protein 60 (HSP60) serves as a potential target for the sensitization of chemoresistant ovarian cancer cells. Gynecol Oncol 2018; 149: 72-3.
Huang L, Yu Z, Zhang T, Zhao X, Huang G. HSP40 interacts with pyruvate kinase m2 and regulates glycolysis and cell proliferation in tumor cells. PLoS One 2014; 9: e92949.
Chen YS, Chang CW, Tsay YG, et al. HSP40 co-chaperone protein Tid1 suppresses metastasis of head and neck cancer by inhibiting Galectin-7-TCF3-MMP9 axis signaling. Theranostics 2018; 8: 3841-55.
Wang TH, Lin YH, Yang SC, et al. Tid1-S regulates the mitochondrial localization of EGFR in non-small cell lung carcinoma. Oncogenesis 2017; 6: e361.
Moses MA, Kim YS, Rivera-Marquez GM, et al. Targeting the Hsp40/Hsp70 chaperone axis as a novel strategy to treat castration-resistant prostate cancer. Cancer Res 2018; 78(14): 4022-35.
Carra S, Alberti S, Arrigo PA, et al. The growing world of small heat shock proteins: from structure to functions. Cell Stress Chaperones 2017; 22(4): 601-11.
Fu X. Chaperone function and mechanism of small heat-shock proteins. Acta Biochim Biophys Sin 2014; 46: 347-56.
Golenhofen N, Bartelt-Kirbach B. The impact of small heat shock proteins (hspbs) in alzheimer’s and other neurological diseases. Curr Pharm Des 2016; 22: 4050-62.
Cox D, Selig E, Griffin MDW, Carver JA, Ecroyd H. Small heat-shock proteins prevent α-synuclein aggregation via transient interactions and their efficacy is affected by the rate of aggregation. J Biol Chem 2016; 291: 22618-29.
Matsumoto T, Urushido M, Ide H, et al. Small heat shock protein beta-1 (hspb1) is upregulated and regulates autophagy and apoptosis of renal tubular cells in acute kidney injury. PLoS One 2015; 10: e0126229.
Kennedy D, Mnich K, Oommen D, et al. HSPB1 facilitates ERK-mediated phosphorylation and degradation of BIM to attenuate endoplasmic reticulum stress-induced apoptosis. Cell Death & Amp Dis 2017; 8: e3026.
Vahid S, Thaper D, Gibson KF, Bishop JL, Zoubeidi A. Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer. Sci Rep 2016; 6: 31842.
Hansen RK, Parra I, Lemieux P, et al. Hsp27 overexpression inhibits doxorubicin-induced apoptosis in human breast cancer cells. Breast Cancer Res Treat 1999; 56: 187-96.
Shaw-Hallgren G, Chmielarska Masoumi K, Zarrizi R, et al. Association of nuclear-localized nemo-like kinase with heat-shock protein 27 inhibits apoptosis in human breast cancer cells. PLoS One 2014; 9: e96506.
Concannon CG, Gorman AM, Samali A. On the role of Hsp27 in regulating apoptosis. Apoptosis 2003; 8: 61-70.
Ghosh A, Lai C, McDonald S, et al. HSP27 expression in primary colorectal cancers is dependent on mutation of KRAS and PI3K/AKT activation status and is independent of TP53. Exp Mol Pathol 2013; 94: 103-8.
Kang SH, Kang KW, Kim K-H, et al. Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability. BMC Cancer 2008; 8: 286.
Stope MB, Wiegank L, Weiss M, et al. Drug-induced modulation of heat shock protein hspb1 in an ovarian cancer cell model. Anticancer Res 2016; 36: 3321-7.
Stope MB, Klinkmann G, Diesing K, et al. Heat shock protein hsp27 secretion by ovarian cancer cells is linked to intracellular expression levels, occurs independently of the endoplasmic reticulum pathway and hsp27's phosphorylation status, and is mediated by exosome liberation. Dis Markers 2017; 2017: 12.
Eto D, Hisaka T, Horiuchi H, et al. Expression of HSP27 in Hepatocellular Carcinoma. Anticancer Res 2016; 36: 3775-9.
Arrigo A-P. Anti-apoptotic, Tumorigenic and metastatic potential of Hsp27 (HspB1) and αB-crystallin (HspB5): emerging targets for the development of new anti-cancer therapeutic strategies. in: calderwood sk, sherman my, ciocca dr, editors. heat shock proteins in cancer. Dordrecht: Springer Netherlands 2007; 73-92.
Bausero MA, Page DT, Osinaga E, Asea A. Surface expression of Hsp25 and Hsp72 differentially regulates tumor growth and metastasis. Tumour Biol 2004; 25: 243-51.
Bausero MA, Bharti A, Page DT, et al. Silencing the hsp25 gene eliminates migration capability of the highly metastatic murine 4T1 breast adenocarcinoma cell. Tumour Biol 2006; 27: 17-26.
Lemieux P, Oesterreich S, Lawrence JA, et al. The small heat shock protein hsp27 increases invasiveness but decreases motility of breast cancer cells. Invasion Metastasis 1997; 17: 113-23.
Gibert B, Eckel B, Gonin V, et al. Targeting heat shock protein 27 (HspB1) interferes with bone metastasis and tumour formation in vivo. Br J Cancer 2012; 107: 63-70.
Fanelli MA, Montt-Guevara M, Diblasi AM, et al. P-cadherin and beta-catenin are useful prognostic markers in breast cancer patients; beta-catenin interacts with heat shock protein Hsp27. Cell Stress Chaperones 2008; 13: 207-20.
Xu L, Chen S, Bergan RC. MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene 2006; 25: 2987.
Sheng B, Qi C, Liu B, et al. Increased HSP27 correlates with malignant biological behavior of non-small cell lung cancer and predicts patient’s survival. Sci Rep 2017; 7: 13807.
Cheng J, Lv Z, Weng X, et al. Hsp27 acts as a master molecular chaperone and plays an essential role in hepatocellular carcinoma progression. Digestion 2015; 92: 192-202.
Illam SP, Narayanankutty A, Mathew SE, et al. Epithelial mesenchymal transition in cancer progression: prev entive phytochemicals. Recent Patents Anticancer Drug Discov 2017; 12: 234-46.
Illam SP, Narayanankutty A, Raghavamenon AC. Polyphenols of virgin coconut oil prevent pro-oxidant mediated cell death. Toxicol Mech Methods 2017; 27: 442-50.
Roy N, Davis S, Narayanankutty A, et al. Garlic Phytocompounds possess anticancer activity by specifically targeting breast cancer biomarkers - an in silico study. Asian Pac J Cancer Prev 2016; 17: 2883-8.
Roy N, Narayanankutty A, Nazeem PA, et al. Plant phenolics ferulic acid and p-coumaric acid inhibit colorectal cancer cell proliferation through EGFR down-regulation. Asian Pac J Cancer Prev 2016; 17: 4019-23.
Roy N, Nazeem PA, Babu TD, et al. EGFR gene regulation in colorectal cancer cells by garlic phytocompounds with special emphasis on S-Allyl-L-Cysteine Sulfoxide. Interdiscip Sci 2017; 10(4): 686-93.
Shweta M, Arunaksharan N. Traditional fruits of kerala: bioactive compounds and their curative potential in chronic diseases. Curr Nutr Food Sci 2017; 13: 279-89.
Prodromou C, Roe SM, O’Brien R, Ladbury JE, Piper PW, Pearl LH. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 1997; 90: 65-75.
Stebbins CE, Russo AA, Schneider C, et al. Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 1997; 89(2): 239-50.
Jang WJ, Jung SK, Kang JS, et al. Anti-tumor activity of WK88-1, a novel geldanamycin derivative, in gefitinib-resistant non-small cell lung cancers with Met amplification. Cancer Sci 2014; 105: 1245-53.
Reka AK, Kuick R, Kurapati H, et al. Identifying inhibitors of epithelial-mesenchymal transition by connectivity map-based systems approach. J Thorac Oncol 2011; 6: 1784-92.
Francis LK, Alsayed Y, Leleu X, et al. Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma. Clin Cancer Res 2006; 12: 6826-35.
Ding G, Feng C, Jiang H, et al. Combination of rapamycin, ci-1040, and 17-aag inhibits metastatic capacity of prostate cancer via slug inhibition. PLoS One 2013; 8: e77400.
Eccles SA, Massey A, Raynaud FI, et al. NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 2008; 68: 2850-60.
Kong A, Rea D, Ahmed S, et al. Phase 1B/2 study of the HSP90 inhibitor AUY922 plus trastuzumab in metastatic HER2-positive breast cancer patients who have progressed on trastuzumab-based regimen. Oncotarget 2016; 7(25): 37680-92.
Duerfeldt AS, Brandt GE, Blagg BS. Design, synthesis, and biological evaluation of conformationally constrained cis-amide Hsp90 inhibitors. Org Lett 2009; 11: 2353-6.
Proia DA, Zhang C, Sequeira M, et al. Preclinical Activity profile and therapeutic efficacy of the hsp90 inhibitor ganetespib in triple-negative breast cancer. Clin Cancer Res 2014; 20: 413-24.
Cameron DA, Spector N, Cortes J, et al. Targeting HSP90 in breast cancer: Enchant-1 (NCT01677455) phase 2 proof of concept study of ganetespib in first-line treatment of women with metastatic breast cancer. J Clin Oncol 2014; 32 TPS665-TPS.
Jhaveri K, Wang R, Teplinsky E, et al. A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer. Breast Cancer Res 2017; 19: 89.
Cercek A, Shia J, Gollub M, et al. Ganetespib, a novel hsp90 inhibitor in patients with kras mutated and wild type, refractory metastatic colorectal cancer. Clin Colorectal Cancer 2014; 13: 207-12.
Ganji PN, Diaz R, El-Rayes B. Antiangiogenic activity of the HSP90 inhibitor ganetespib in pancreatic cancer models. FASEB J 2013; 27: lb572-lb.
Nagaraju GP, Park W, Wen J, et al. Antiangiogenic effects of ganetespib in colorectal cancer mediated through inhibition of HIF-1alpha and STAT-3. Angiogenesis 2013; 16(4): 903-17.
Xiang L, Gilkes DM, Chaturvedi P, et al. Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer. J Mol Med 2014; 92: 151-64.
Meehan R, Kummar S, Do K, et al. A Phase i study of ganetespib and ziv‐aflibercept in patients with advanced carcinomas and sarcomas. Oncologist 2018; 23(11): 1269-e125.
Jiang J, Lu Y, Li Z, et al. Ganetespib overcomes resistance to PARP inhibitors in breast cancer by targeting core proteins in the DNA repair machinery. Invest New Drugs 2017; 35: 251-9.
Chatterjee S, Huang EH, Christie I, Kurland BF, Burns TF. Acquired Resistance to the hsp90 inhibitor, ganetespib, in kras-mutant nsclc is mediated via reactivation of the erk-p90rsk-mtor signaling network. Mol Cancer Ther 2017; 16: 793-804.
Yim KH, Prince TL, Qu S, et al. Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90beta. Proc Natl Acad Sci USA 2016; 113(33): E4801-9.
Wang X, Chen W. Gambogic acid is a novel anti-cancer agent that inhibits cell proliferation, angiogenesis and metastasis. Anticancer Agents Med Chem 2012; 12: 994-1000.
Zhao K, Zhang S, Song X, et al. Gambogic acid suppresses cancer invasion and migration by inhibiting TGFbeta1-induced epithelial-to-mesenchymal transition. Oncotarget 2017; 8: 27120-36.
Massey AJ, Williamson DS, Browne H, et al. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 2010; 66(3): 535-45.
Zhang L, Fok JJL, Mirabella F, et al. Hsp70 inhibition induces myeloma cell death via the intracellular accumulation of immunoglobulin and the generation of proteotoxic stress. Cancer Lett 2013; 339: 49-59.
Tang X, Tan L, Shi K, et al. Gold nanorods together with HSP inhibitor-VER-155008 micelles for colon cancer mild-temperature photothermal therapy. Acta Pharmaceutica Sinica B 2018; 8: 587-601.
Brodsky JL. Selectivity of the molecular chaperone-specific immunosuppressive agent 15-deoxyspergualin: modulation of Hsc70 ATPase activity without compromising DnaJ chaperone interactions. Biochem Pharmacol 1999; 57(8): 877-80.
Dhingra K, Valero V, Gutierrez L, et al. Phase II study of deoxyspergualin in metastatic breast cancer. Invest New Drugs 1994; 12: 235-41.
Divgi CR, Scott AM, Gulec S, et al. Pilot radioimmunotherapy trial with 131I-labeled murine monoclonal antibody CC49 and deoxyspergualin in metastatic colon carcinoma. Clin Cancer Res 1995; 1: 1503-10.
Wadhwa R, Sugihara T, Yoshida A, et al. Selective Toxicity of mkt-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. Cancer Res 2000; 60(24): 6818-21.
Starenki D, Park JI. Selective mitochondrial uptake of mkt-077 can suppress medullary thyroid carcinoma cell survival in vitro and in vivo. Endocrinol Metab 2015; 30: 593-603.
Tran PL, Kim SA, Choi HS, Yoon JH, Ahn SG. Epigallocatechin-3-gallate suppresses the expression of HSP70 and HSP90 and exhibits anti-tumor activity in vitro and in vivo. BMC Cancer 2010; 10: 1471-2407.
Moses MA, Henry EC, Ricke WA, Gasiewicz TA. The heat shock protein 90 inhibitor, (-)-epigallocatechin gallate, has anticancer activity in a novel human prostate cancer progression model. Cancer Prev Res 2015; 8: 249-57.
Maruyama T, Murata S, Nakayama K, et al. (-)-Epigallocatechin-3-gallate suppresses liver metastasis of human colorectal cancer. Oncol Rep 2014; 31: 625-33.
Rady I, Mohamed H, Rady M, Siddiqui IA, Mukhtar H. Cancer preventive and therapeutic effects of EGCG, the major polyphenol in green tea. Egyptian J Basic Applied Sci 2018; 5: 1-23.
Qiu X, Yuan Y, Vaishnav A, et al. Effects of lycopene on protein expression in human primary prostatic epithelial cells. Cancer Prev Res 2013; 6(5): 419-27.
Palozza P, Simone R, Catalano A, et al. Lycopene prevents 7-ketocholesterol-induced oxidative stress, cell cycle arrest and apoptosis in human macrophages. J Nutr Biochem 2010; 21: 34-46.
Elia G, Santoro MG. Regulation of heat shock protein synthesis by quercetin in human erythroleukaemia cells. Biochem J 1994; 300: 201-9.
Storniolo A, Raciti M, Cucina A, Bizzarri M, Di Renzo L. Quercetin Affects Hsp70/IRE1α; mediated protection from death induced by endoplasmic reticulum stress. Oxid Med Cell Longev 2015; 2015: 11.
Yang W, Cui M, Lee J, et al. Heat shock protein inhibitor, quercetin, as a novel adjuvant agent to improve radiofrequency ablation-induced tumor destruction and its molecular mechanism. Chin J Cancer Res 2016; 28: 19-28.
Heinrich JC, Donakonda S, Haupt VJ, Lennig P, Zhang Y, Schroeder M. New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells. Oncotarget 2016; 7: 68156-69.
Lamoureux F, Thomas C, Yin M-J, et al. Suppression of heat shock protein 27 using ogx-427 induces endoplasmic reticulum stress and potentiates heat shock protein 90 inhibitors to delay castrate-resistant prostate cancer. Eur Urol 2014; 66(1): 145-55.
Chi KN, Yu EY, Jacobs C, et al. A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers. Ann Oncol 2016; 27: 1116-22.
Bellmunt J, Eigl BJ, Senkus E, et al. Borealis-1: a randomized, first-line, placebo-controlled, phase II study evaluating apatorsen and chemotherapy for patients with advanced urothelial cancer. Ann Oncol 2017; 28(10): 2481-8.
Choueiri TK, Hahn NM, Werner L, Regan MM, Rosenberg JE. Borealis-2: A randomized phase II study of OGX-427 (apatorsen) plus docetaxel versus docetaxel alone in platinum-resistant metastatic urothelial cancer (mUC) (Hoosier Cancer Research Network GU12-160). J Clin Oncol 2017; 35(6): 289-9.
Ko AH, Murphy PB, Peyton JD, et al. A randomized, double-blinded, phase ii trial of gemcitabine and nab-paclitaxel plus apatorsen or placebo in patients with metastatic pancreatic cancer: the rainier trial. Oncologist 2017; 22: 2017-0066.
Callebaut I, Catelli MG, Portetelle D, et al. Structural similarities between chaperone molecules of the HSP60 and HSP70 families deduced from hydrophobic cluster analysis. FEBS Lett 1994; 342: 242-8.
Lee C, Park HK, Jeong H, et al. Development of a mitochondria-targeted Hsp90 inhibitor based on the crystal structures of human TRAP1. J Am Chem Soc 2015; 137: 4358-67.
Fiesel FC, James ED, Hudec R, Springer W. Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy. Oncotarget 2017; 8: 106233-48.
Liu J, Liu J, Guo S-Y, Liu H-L, Li S-Z. HSP70 inhibitor combined with cisplatin suppresses the cervical cancer proliferation in vitro and transplanted tumor growth: An experimental study. Asian Pacific J Tropical Med 2017; 10(2): 184-8.
Ma L, Sato F, Sato R, et al. Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer. Oncol Rep 2014; 31(6): 2482-92.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [727 - 737]
Pages: 11
DOI: 10.2174/1389450120666181211111815
Price: $65

Article Metrics

PDF: 31