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Xiong, J.;  Li, Y.;  Tan, X.;  Fu, L. Small Heat Shock Proteins in Cancer Therapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/27505 (accessed on 25 April 2024).
Xiong J,  Li Y,  Tan X,  Fu L. Small Heat Shock Proteins in Cancer Therapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/27505. Accessed April 25, 2024.
Xiong, Jixian, Yuting Li, Xiangyu Tan, Li Fu. "Small Heat Shock Proteins in Cancer Therapy" Encyclopedia, https://encyclopedia.pub/entry/27505 (accessed April 25, 2024).
Xiong, J.,  Li, Y.,  Tan, X., & Fu, L. (2022, September 23). Small Heat Shock Proteins in Cancer Therapy. In Encyclopedia. https://encyclopedia.pub/entry/27505
Xiong, Jixian, et al. "Small Heat Shock Proteins in Cancer Therapy." Encyclopedia. Web. 23 September, 2022.
Small Heat Shock Proteins in Cancer Therapy
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This entry is adapted from the peer-reviewed paper 10.3390/ijms21186611

Small heat shock proteins (sHSPs) are ubiquitous ATP-independent chaperones that play essential roles in response to cellular stresses and protein homeostasis. sHSPs are ubiquitously expressed in numerous types of tumors, and their expression is closely associated with cancer progression. sHSPs have been suggested to control a diverse range of cancer functions, including tumorigenesis, cell growth, apoptosis, metastasis, and chemoresistance, as well as regulation of cancer stem cell properties. 

sHSPs cancer cancer stem cells cancer therapy

 1. Anticancer Drugs Targeting sHSPs

As a majority of clinical and preclinical findings indicate sHSPs as a promising therapeutic target in cancer, a number of drugs or inhibitors have been reported and utilized to interrogate sHSPs’ roles in cancer. The reports are mainly focused on HspB1 as a molecular target for cancer therapy. Hence, in the present subsection, the drugs targeting HspB1 are analyzed in more detail. Although several drugs or compounds for other sHSPs in cancer therapy have been described, other sHSPs are omitted here because no selective inhibitors targeting these sHSPs have been reported.
The drugs aimed at reducing HspB1 expression or inhibiting its actions in cancer therapy (Table 1). Small molecule inhibitors (RP101, quercetin, J2, ovatodiolide, and methyl antcinate) bind to the HspB1 protein and inhibit its function. Another strategy utilizes peptide aptamers (PA11, PA50) that bind directly to the protein and inhibit its oligomerization or dimerization. Moreover, the third approach is antisense oligonucleotide (OGX-427), which targets HspB1 mRNA and prevents translation of the protein.
Table 1. Summary of reported cancer drugs targeting HspB1.
Types Names Mechanism Binding Sites Reference
Small Molecules RP101 Binds to HspB1 protein and inhibits
HspB1 function		 Phe29 and Phe33 [1][2][3][4][5]
quercetin No data available [6][7][8][9][10][11][12][13][14][15]
J2 Cysteine thiol group [16]
ovatodiolide No data available [17]
methyl antcinate No data available [18]
Peptide Aptamers PA11 Binds to HspB1 protein and inhibits its oligomerization or dimerization No data available [19][20][21]
PA50 No data available
Antisence Oligonucleotide OGX-427 Binds to HspB1 mRNA and prevents translation of the protein No data available [22][23][24][25][26]
Several small molecule inhibitors targeting HspB1 are currently under development: RP101, quercetin, J2, ovatodiolide, and methyl antcinate. RP101 (also known as bromovinyldeoxyuridine, BVDU, or brivudine) is a nucleoside that inhibits HspB1 function via binding with Phe29 and Phe33 of HspB1. RP101 functions as a chemo-sensitizing agent that inhibits the resistance and potentiates the effects of many chemotherapeutic drugs including mitomycin [1][2], gemcitabine [2][3], cisplatin [2][3], and cyclophosphamide [2]. In clinical studies, RP101 [2][3] or RP101 with gemcitabine [3][4] increased the overall survival rate of pancreatic cancer patients. However, overdosing of RP101 caused increased toxic side effects of gemcitabine in some patients [2], and new second-generation candidates of RP101 have been identified and are being developed for further evaluation [5]. Quercetin is a plant-derived bioflavonoid with anticancer properties [8]. It suppresses the HSF1-dependent induction of the Hsps and shows antitumor effects in gastric, oral, lymphomas, prostate, colorectal, breast, pancreatic, liver, and lung cancer cell lines and various cancer stem cells [9][10][11][12]. Quercetin can act as a chemo-sensitizer, and it enhances the antitumor effects of first-line chemotherapeutic drugs such as doxorubicin, gemcitabine, 5-fluorouracil, and cisplatin [13][14]. Interestingly, besides its inhibitory effect on HspB1 expression, quercetin can suppress HspB1 activity by impairing its phosphorylation in CSCs [7]. Despite studies showing that quercetin can be a suitable agent for cancer treatment, there are no ongoing anticancer trials for quercetin. J2, a synthetic chromone compound, can induce the crosslinking of HspB1 protein and form HspB1 abnormal dimerization, thereby inhibiting its functions [15]. Recently, ovatodiolide [6] and methyl antcinate [16], two plant-derived compounds, have been reported to decrease HspB1 protein expression in breast CSCs and inhibit CSCs. It has to be elucidated whether these compounds are clinically applicable against breast cancer.
The second approach to targeting HspB1 is the use of specific peptides, which are called peptide aptamers, to bind the protein and inhibit the functions of HspB1. Peptide aptamers are short peptides that are designed to bind to specific protein domains and disrupt the protein function. Recent research showed that two peptide aptamers, PA11 and PA50, can specifically bind to HspB1, inhibiting HspB1 dimerization or oligomerization, thereby negatively modulating the functions of HspB1 [17]. These peptide aptamers are reported to show antitumor effects in vitro [17] and in vivo [18]. Similar to the small molecule inhibitors of HspB1, a peptide aptamer is always more effective when used with other anticancer drugs than when used alone. More efforts are needed to promote the preclinical and clinical application of peptide aptamers and provide a potential application to cancer therapy.
The third approach utilizes antisense oligonucleotide (ASO) targeting HspB1 mRNA, and OGX-427, which prevents the expression of HspB1 protein. OGX-427 reduced xenograft tumor growth when used in combination with chloroquine [19] or gemcitabine, respectively [20], compared to treatment with the drug alone. The Phase I study of dose-escalation OGX-427 in prostate, bladder, breast, and lung cancers showed that OGX-427 was well tolerated at a high dose (1000 mg), and it can decrease tumor marker expression and the number of circulating tumor cells (CTCs) in patients with prostate and ovarian cancers [21]. In a Phase II trial for castrate-resistant prostate cancer (CRPC), 71% of patients treated with OGX-427 and prednisone were progression-free at 12 weeks, compared to 40% of patients treated with prednisone alone [22]. However, in another Phase II trial for metastatic non-small-cell lung cancer (NSCLC), the addition of OGX-427 to the carboplatin–pemetrexed regimen did not improve outcomes and the efficacy of first-line chemotherapy for patients [23]. More clinical studies are needed to evaluate the efficacy and side effects of OGX-427 as a combinational clinical therapy in the treatment of different cancer patients.

2. sHSPs-Based Cancer Therapy

Other than a molecular target for cancer therapy, sHsps have been reported to be used as a multifunctional scaffold for the targeted therapeutic and imaging systems in cancers. The naturally occurring small heat shock protein 16.5, which originates from Methanocaldococcus jannaschii, is reported to form a cage-like structure to act as multifunctional biomaterials. The genetically and chemically modified Hsp16.5 cages, Cy5.5-HspDEVD-BHQ3, were developed for imaging caspase activity in vitro and in vivo [24]. Thus, these sHsp cages may provide efficient imaging agent carriers to monitor the therapeutic evaluation by imaging caspase activity within tumors. Similarly, Hsp16.5-based nanocages, conjugated with gadolinium (III)-chelated agents and iRGD peptides, were developed for the diagnosis of pancreatic cancers by magnetic resonance imaging (MRI) [25]. It showed that sHsps have great potential in the diagnosis of cancers as a carrier to construct a specific and sensitive MRI contrast agent. Moreover, Hsp16.5-based cages carrying doxorubicin (an anticancer agent) were tested in various cancer cell lines [26] and could provide a useful drug delivery system in cancer therapy. As sHsps cages have good biocompatibility, biodegradability, and easy fabrication, they may be promising as biomedical materials for drug or imaging agent delivery in cancer therapy and other biomedical applications.

References

  1. Fahrig, R.; Heinrich, J.C.; Nickel, B.; Wilfert, F.; Leisser, C.; Krupitza, G.; Praha, C.; Sonntag, D.; Fiedler, B.; Scherthan, H.; et al. Inhibition of induced chemoresistance by cotreatment with (E)-5-(2-bromovinyl)-2′-deoxyuridine (RP101). Cancer Res. 2003, 63, 5745–5753.
  2. Heinrich, J.C.; Tuukkanen, A.; Schroeder, M.; Fahrig, T.; Fahrig, R. RP101 (brivudine) binds to heat shock protein HSP27 (HSPB1) and enhances survival in animals and pancreatic cancer patients. J. Cancer Res. Clin. Oncol. 2011, 137, 1349–1361.
  3. Fahrig, R.; Quietzsch, D.; Heinrich, J.C.; Heinemann, V.; Boeck, S.; Schmid, R.M.; Praha, C.; Liebert, A.; Sonntag, D.; Krupitza, G.; et al. RP101 improves the efficacy of chemotherapy in pancreas carcinoma cell lines and pancreatic cancer patients. Anticancer Drugs 2006, 17, 1045–1056.
  4. Hidalgo, M. Phase II Study to Evaluate Efficacy and Safety of RP101 in Combination With Gemcitabine (RP101). Available online: https://clinicaltrials.gov/ct2/show/NCT00550004?term=NCT00550004 (accessed on 10 August 2020).
  5. Fahrig, R.; Kutz, K.; Heinrich, J.C.; Fahrig, T.; Koch, A. 2nd Generation Product Candidates. Available online: https://resprotect.de/2nd-Generation-Product-Candidates/2nd-Generation-Product-Candidates.html (accessed on 10 August 2020).
  6. Lu, K.T.; Wang, B.Y.; Chi, W.Y.; Chang-Chien, J.; Yang, J.J.; Lee, H.T.; Tzeng, Y.M.; Chang, W.W. Ovatodiolide inhibits breast cancer stem/progenitor cells through SMURF2-mediated downregulation of Hsp27. Toxins 2016, 8, 127.
  7. Chen, S.F.; Nieh, S.; Jao, S.W.; Liu, C.L.; Wu, C.H.; Chang, Y.C.; Yang, C.Y.; Lin, Y.S. Quercetin suppresses drug-resistant spheres via the p38 MAPK–Hsp27 apoptotic pathway in oral cancer cells. PLoS ONE 2012, 7, e49275.
  8. Reyes-Farias, M.; Carrasco-Pozo, C. The anti-cancer effect of quercetin: Molecular implications in cancer metabolism. Int. J. Mol. Sci. 2019, 20, 3177.
  9. Vafadar, A.; Shabaninejad, Z.; Movahedpour, A.; Fallahi, F.; Taghavipour, M.; Ghasemi, Y.; Akbari, M.; Shafiee, A.; Hajighadimi, S.; Moradizarmehri, S.; et al. Quercetin and cancer: New insights into its therapeutic effects on ovarian cancer cells. Cell BioSci. 2020, 10, 32.
  10. Erdogan, S.; Turkekul, K.; Dibirdik, I.; Doganlar, O.; Doganlar, Z.B.; Bilir, A.; Oktem, G. Midkine downregulation increases the efficacy of quercetin on prostate cancer stem cell survival and migration through PI3K/AKT and MAPK/ERK pathway. Biomed. Pharmacother. 2018, 107, 793–805.
  11. Wang, R.; Yang, L.; Li, S.; Ye, D.; Yang, L.; Liu, Q.; Zhao, Z.; Cai, Q.; Tan, J.; Li, X. Quercetin inhibits breast cancer stem cells via downregulation of aldehyde dehydrogenase 1A1 (ALDH1A1), chemokine receptor type 4 (CXCR4), Mucin 1 (MUC1), and epithelial cell adhesion molecule (EpCAM). Med. Sci. Monit. 2018, 24, 412–420.
  12. Cao, C.; Sun, L.; Mo, W.; Sun, L.; Luo, J.; Yang, Z.; Ran, Y. Quercetin mediates β-catenin in pancreatic cancer stem-like cells. Pancreas 2015, 44, 1334–1339.
  13. Staedler, D.; Idrizi, E.; Kenzaoui, B.H.; Juillerat-Jeanneret, L. Drug combinations with quercetin: Doxorubicin plus quercetin in human breast cancer cells. Cancer Chemother. Pharmacol. 2011, 68, 1161–1172.
  14. Xavier, C.P.; Lima, C.F.; Rohde, M.; Pereira-Wilson, C. Quercetin enhances 5-fluorouracil-induced apoptosis in MSI colorectal cancer cells through p53 modulation. Cancer Chemother. Pharmacol. 2011, 68, 1449–1457.
  15. Choi, B.; Choi, S.K.; Park, Y.N.; Kwak, S.Y.; Lee, H.J.; Kwon, Y.; Na, Y.; Lee, Y.S. Sensitization of lung cancer cells by altered dimerization of HSP27. Oncotarget 2017, 8, 105372–105382.
  16. Peng, C.Y.; Fong, P.C.; Yu, C.C.; Tsai, W.C.; Tzeng, Y.M.; Chang, W.W. Methyl antcinate a suppresses the population of cancer stem-like cells in MCF7 human breast cancer cell line. Molecules 2013, 18, 2539–2548.
  17. Gibert, B.; Hadchity, E.; Czekalla, A.; Aloy, M.T.; Colas, P.; Rodriguez-Lafrasse, C.; Arrigo, A.P.; Diaz-Latoud, C. Inhibition of heat shock protein 27 (HspB1) tumorigenic functions by peptide aptamers. Oncogene 2011, 34, 3672–3681.
  18. Gibert, B.; Simon, S.; Dimitrova, V.; Diaz-Latoud, C.; Arrigo, A.P. Peptide aptamers: Tools to negatively or positively modulate HSPB1(27) function. Philos. Trans. R. Soc. B 2013, 368, 0120075.
  19. Kumano, M.; Furukawa, J.; Shiota, M.; Zardan, A.; Zhang, F.; Beraldi, E.; Wiedmann, R.M.; Fazli, L.; Zoubeidi, A.; Gleave, M.E. Cotargeting stress-activated Hsp27 and autophagy as a combinatorial strategy to amplify endoplasmic reticular stress in prostate cancer. Mol. Cancer Ther. 2012, 11, 1661–1671.
  20. Lelj-Garolla, B.; Kumano, M.; Beraldi, E.; Nappi, L.; Rocchi, P.; Ionescu, D.N.; Fazli, L.; Zoubeidi, A.; Gleave, M.E. Hsp27 Inhibition with OGX-427 sensitizes non-small cell lung cancer cells to erlotinib and chemotherapy. Mol. Cancer Ther. 2015, 14, 1107–1116.
  21. Chi, K.N.; Yu, E.Y.; Jacobs, C.; Bazov, J.; Kollmannsberger, C.; Higano, C.S.; Mukherjee, S.D.; Gleave, M.E.; Stewart, P.S.; Hotte, S.J. 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, 1116–1122.
  22. Chi, K.N.; Hotte, S.J.; Ellard, S.; Gingerich, J.R.; Joshua, A.M.; Kollmannsberger, C.K.; Yu, E.Y.; Gleave, M.E. A randomized phase II study of OGX-427 plus prednisone versus prednisone alone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. J. Clin. Oncol. 2012, 30, 121.
  23. Spigel, D.R.; Shipley, D.L.; Waterhouse, D.M.; Jones, S.F.; Ward, P.J.; Shih, K.C.; Hemphill, B.; McCleod, M.; Whorf, R.C.; Page, R.D.; et al. A randomized, double-blinded, phase II trial of carboplatin and pemetrexed with or without Apatorsen (OGX-427) in patients with previously untreated stage IV non-squamous-non-small-cell lung cancer: The SPRUCE Trial. Oncologist 2019, 24, e1409–e1416.
  24. Choi, S.H.; Kwon, I.C.; Hwang, K.Y.; Kim, I.S.; Ahn, H.J. Small heat shock protein as a multifunctional scaffold: Integrated tumor targeting and caspase imaging within a single cage. Biomacromolecules 2011, 12, 3099–3106.
  25. Kawano, T.; Murata, M.; Kang, J.H.; Piao, J.S.; Narahara, S.; Hyodo, F.; Hamano, N.; Guo, J.; Oguri, S.; Ohuchida, K.; et al. Ultrasensitive MRI detection of spontaneous pancreatic tumors with nanocage-based targeted contrast agent. Biomaterials 2018, 152, 37–46.
  26. Toita, R.; Murata, M.; Abe, K.; Narahara, S.; Piao, J.S.; Kang, J.H.; Ohuchida, K.; Hashizume, M. Biological evaluation of protein nanocapsules containing doxorubicin. Int. J. Nanomed. 2013, 8, 1989–1999.
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Subjects: Oncology; Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Jixian Xiong
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Yuting Li
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Xiangyu Tan
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Li Fu
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Update Date: 23 Sep 2022
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