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Debio-0932, a second generation oral Hsp90 inhibitor, induces apoptosis in MCF-7 and MDA-MB-231 cell lines

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Abstract

Heat shock protein 90 (Hsp90) is a key chaperone that is abnormally expressed in cancer cells, and therefore, designing novel compounds to inhibit chaperone activities of the Hsp90 is a promising therapeutic approach for cancer drug discovery. Debio-0932 is a second-generation Hsp90 inhibitor that exhibited promising anticancer activity against a wide variety of cancer types with a strong binding affinity for Hsp90 and high oral bioavailability. Anticancer activities of the Debio-0932 were tested in MCF-7 and MDA-MB-231 cell lines. Molecular docking results indicated that Debio-0932 was selectively bound to the ATP binding pocket of the Hsp90 with an estimated free energy of binding − 7.24 kcal/mol. Antiproliferative activity of Debio-0932 was determined by XTT assay and Debio-0932 exhibited a cytotoxic effect on MCF-7 and MDA-MB-231 cells in a time and dose-depended manner. Apoptosis inducer role of Debio-0932 was evaluated in MCF-7 and MDA-MB-231 cells with fluorometric apoptosis/necrosis detection kit. Treatment with Debio-0932 stimulated apoptosis in both breast cancer cell lines. mRNA and protein expression levels of Bax, Bcl-2 and Casp-9 were determined in MCF-7 and MDA-MB-231 cells by RT-PCR and Western blotting respectively. Debio-0932 stimulated the down-regulation of anti-apoptotic protein Bcl-2 and the up-regulation of apoptotic protein Bax and cleavage of Casp-9 in cancer cells. Moreover, the anti-invasive potential of Debio-0932 was evaluated in endothelial cells (HUVEC) by wound-healing assay. Debio-0932 decreased the migration of HUVEC cells as compared to the control group. These results indicate that Debio-0932 is a promising compound to treat triple-negative breast cancer and hormone receptor-positive breast cancer, and their metastases.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    PubMed  Google Scholar 

  2. Austin D, Hamilton N, Elshimali Y, Pietras R, Wu Y, Vadgama J (2018) Oestrogen receptor-beta is a potential target for triple negative breast cancer treatment. Oncotarget 9:33912–33930

    PubMed  PubMed Central  Google Scholar 

  3. Hussain SA, Palmer DH, Stevens A, Spooner D, Poole CJ, Rea DW (2005) Role of chemotherapy in breast cancer. Expert Rev Anticancer Ther 5:1095–1110

    CAS  PubMed  Google Scholar 

  4. Van den Berg MM, Winkels RM, de Kruif JT, van Laarhoven HW, Visser M, de Vries JH et al (2017) Weight change during chemotherapy in breast cancer patients: a meta-analysis. BMC Cancer 17:1–13

    Google Scholar 

  5. Ozgur A, Tutar Y (2016) Heat shock protein 90 inhibition in cancer drug discovery: from chemistry to futural clinical applications. Anti-Cancer Agents Med Chem 16:280–290

    CAS  Google Scholar 

  6. Gümus M, Ozgur A, Tutar L, Disli A, Koca I, Tutar Y (2016) Design, synthesis, and evaluation of heat shock protein 90 inhibitors in human breast cancer and its metastasis. Curr Pharm Biotechnol 17:1231–1245

    PubMed  Google Scholar 

  7. Zagouri F, Bournakis E, Koutsoukos K, Papadimitriou CA (2012) Heat shock protein 90 (hsp90) expression and breast cancer. Pharmaceuticals (Basel) 5:1008–1020

    CAS  Google Scholar 

  8. Zagouri F, Sergentanis TN, Chrysikos D, Papadimitriou CA, Dimopoulos MA, Psaltopoulou T (2013) Hsp90 inhibitors in breast cancer: a systematic review. Breast 22:569–578

    PubMed  Google Scholar 

  9. Tutar L, Tutar Y (2010) Heat shock proteins; an overview. Curr Pharm Biotechnol 11:216–222

    CAS  PubMed  Google Scholar 

  10. Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86–103

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Zuo D, Subjeck J, Wang XY (2016) Unfolding the role of large heat shock proteins: new insights and therapeutic implications. Front Immunol 7:1–15

    Google Scholar 

  12. Tukaj S, Kaminski M (2019) Heat shock proteins in the therapy of autoimmune diseases: too simple to be true? Cell Stress Chaperones 24(3):475–479

    PubMed  PubMed Central  Google Scholar 

  13. Lyon MS, Milligan C (2019) Extracellular heat shock proteins in neurodegenerative diseases: new perspectives. Neurosci Lett 711:134462

    CAS  PubMed  Google Scholar 

  14. Bolhassani A, Agi E (2019) Heat shock proteins in infection. Clin Chim Acta 498:90–100

    CAS  PubMed  Google Scholar 

  15. Ozgur A, Tutar Y (2014) Heat shock protein 90 inhibitors in oncology. Curr Proteomics 11:2–16

    CAS  Google Scholar 

  16. Tutar L, Ozgur A, Tutar E, Coskun KA, Tutar Y (2014) Heat shock response agents and the diseases. Bentham Science Publishers, Berlin

    Google Scholar 

  17. Carneiro BA, El-Deiry WS (2020) Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol 7:395–417

    Google Scholar 

  18. D’Arcy MS (2019) Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 43(6):582–592

    PubMed  Google Scholar 

  19. Jan R, Chaudhry GE (2019) Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull 9(2):205–218

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Özgür A (2021) Investigation of anticancer activities of STA-9090 (ganetespib) as a second generation HSP90 inhibitor in Saos-2 osteosarcoma cells. J Chemother. https://doi.org/10.1080/1120009X.2021.1908650

    Article  PubMed  Google Scholar 

  21. Li L, Wang L, You QD, Xu XL (2020) Heat shock protein 90 inhibitors: an update on achievements, challenges, and future directions. J Med Chem 63(5):1798–1822

    CAS  PubMed  Google Scholar 

  22. Lanneau D, Brunet M, Frisan E, Solary E, Fontenay M, Garrido C (2008) Heat shock proteins: essential proteins for apoptosis regulation. J Cell Mol Med 12(3):743–761

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Mori M, Hitora T, Nakamura O, Yamagami Y, Horie R, Nishimura H et al (2015) Hsp90 inhibitor induces autophagy and apoptosis in osteosarcoma cells. Int J Oncol 46(1):47–54

    CAS  PubMed  Google Scholar 

  24. Lanneau D, de Thonel A, Maurel S, Didelot C, Garrido C (2007) Apoptosis versus cell differentiation: role of heat shock proteins HSP90, HSP70 and HSP27. Prion 1(1):53–60

    PubMed  PubMed Central  Google Scholar 

  25. Stenderup K, Rosada C, Gavillet B, Vuagniaux G, Dam TN (2014) Debio 0932, a new oral Hsp90 inhibitor, alleviates psoriasis in a xenograft transplantation model. Acta Derm Venereol 94(6):672–676

    PubMed  Google Scholar 

  26. Isambert N, Delord JP, Soria JC, Hollebecque A, Gomez-Roca C, Purcea D et al (2015) Debio0932, a second-generation oral heat shock protein (HSP) inhibitor, in patients with advanced cancer-results of a first-in-man dose-escalation study with a fixed-dose extension phase. Ann Oncol 26(5):1005–1011

    CAS  PubMed  Google Scholar 

  27. Jhaveri K, Taldone T, Modi S (1823) Chiosis G (2012) Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta 3:742–755

    Google Scholar 

  28. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27(3):221–234

    PubMed  Google Scholar 

  29. Westbrook JD, Shao C, Feng Z, Zhuravleva M, Velankar S, Young J (2015) The chemical component dictionary: complete descriptions of constituent molecules in experimentally determined 3D macromolecules in the Protein Data Bank. Bioinformatics 31(8):1274–1278

    PubMed  Google Scholar 

  30. Greenwood JR, Calkins D, Sullivan AP, Shelley JC (2010) Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution. J Comput Aided Mol Des 24(6–7):591–604

    CAS  PubMed  Google Scholar 

  31. Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR et al (2007) a software program for pK(a) prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des 21(12):681–691

    CAS  PubMed  Google Scholar 

  32. Li H, Robertson AD, Jensen JH (2005) Very fast empirical prediction and rationalization of protein pKa values. Proteins 61(4):704–721

    CAS  PubMed  Google Scholar 

  33. Søndergaard CR, Olsson MH, Rostkowski M, Jensen JH (2011) Improved treatment of ligands and coupling effects in empirical calculation and rationalization of pKa values. J Chem Theory Comput 7(7):2284–2295

    PubMed  Google Scholar 

  34. Roos K, Wu C, Damm W, Reboul M, Stevenson JM, Lu C et al (2019) OPLS3e: extending force field coverage for drug-like small molecules. J Chem Theory Comput 15(3):1863–1874

    CAS  PubMed  Google Scholar 

  35. Yao H, He G, Yan S, Chen C, Song L, Rosol TJ et al (2017) Triple-negative breast cancer: is there a treatment on the horizon? Oncotarget 8(1):1913–1924

    PubMed  Google Scholar 

  36. Ghadban T, Jessen A, Reeh M, Dibbern JL, Mahner S, Mueller V et al (2016) In vitro study comparing the efficacy of the water-soluble HSP90 inhibitors, 17-AEPGA and 17-DMAG, with that of the non-water-soluble HSP90 inhibitor, 17-AAG, in breast cancer cell lines. Int J Mol Med 38(4):1296–1302

    CAS  PubMed  Google Scholar 

  37. Taechowisan T, Samsawat T, Puckdee W, Phutdhawong WS (2020) Cytotoxicity activity of geldanamycin derivatives against various cancer cell lines. JAPS 10(06):12–21

    CAS  Google Scholar 

  38. Li Z, Jia L, Wang J, Wu X, Hao H, Wu Y et al (2014) Discovery of diamine-linked 17-aroylamido-17-demethoxygeldanamycins as potent Hsp90 inhibitors. Eur J Med Chem 87:346–363

    CAS  PubMed  Google Scholar 

  39. Chang CH, Drechsel DA, Kitson RR, Siegel D, You Q, Backos DS et al (2014) 19-substituted benzoquinone ansamycin heat shock protein-90 inhibitors: biological activity and decreased off-target toxicity. Mol Pharmacol 85(6):849–857

    PubMed  PubMed Central  Google Scholar 

  40. Friedland JC, Smith DL, Sang J, Acquaviva J, He S, Zhang C et al (2014) Targeted inhibition of Hsp90 by ganetespib is effective across a broad spectrum of breast cancer subtypes. Investig New Drugs 32(1):14–24

    CAS  Google Scholar 

  41. Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J et al (2008) NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 10(2):R33

    PubMed  PubMed Central  Google Scholar 

  42. Proia DA, Zhang C, Sequeira M, Jimenez JP, He S, Spector N et al (2014) Preclinical activity profile and therapeutic efficacy of the HSP90 inhibitor ganetespib in triple-negative breast cancer. Clin Cancer Res 20(2):413–424

    CAS  PubMed  Google Scholar 

  43. Salentin S, Haupt VJ, Daminelli S, Schroeder M (2014) Polypharmacology rescored: protein-ligand interaction profiles for remote binding site similarity assessment. Prog Biophys Mol Biol 116(2–3):174–186

    CAS  PubMed  Google Scholar 

  44. Kurczab R, Śliwa P, Rataj K, Kafel R, Bojarski AJ (2018) Salt bridge in ligand-protein complexes-systematic theoretical and statistical investigations. J Chem Inf Model 58(11):2224–2238

    CAS  PubMed  Google Scholar 

  45. Bhardwaj M, Paul S, Jakhar R, Kang SC (2015) Potential role of vitexin in alleviating heat stress-induced cytotoxicity: regulatory effect of Hsp90 on ER stress-mediated autophagy. Life Sci 142:36–48

    CAS  PubMed  Google Scholar 

  46. Saman H, Raza SS, Uddin S, Rasul K (2020) Inducing angiogenesis, a key step in cancer vascularization, and treatment approaches. Cancers (Basel) 12(5):1172

    CAS  Google Scholar 

  47. Eelen G, Treps L, Li X, Carmeliet P (2020) Basic and therapeutic aspects of angiogenesis updated. Circ Res 127(2):310–329

    CAS  PubMed  Google Scholar 

  48. Teleanu RI, Chircov C, Grumezescu AM, Teleanu DM (2019) Tumor angiogenesis and anti-angiogenic strategies for cancer treatment. J Clin Med 9(1):84

    PubMed Central  Google Scholar 

  49. https://www.picard.ch/downloads/Hsp90interactors.pdf

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Funding

This work was supported by grants from Tokat Gaziosmanpaşa University, Foundation of Scientific Researches Projects (Project Number: 2019/76).

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Authors and Affiliations

  1. Department of Veterinary Medicine, Laboratory and Veterinary Health Program, Artova Vocational School, Tokat Gaziosmanpaşa University, Tokat, Turkey

    Aykut Özgür

  2. TUBITAK Marmara Research Center, Gene Engineering and Biotechnology Institute, Gebze, Turkey

    Altan Kara & Şaban Tekin

  3. Department of Biomaterials and Tissue Engineering, Faculty of Engineering and Architecture, Tokat Gaziosmanpaşa University, Tokat, Turkey

    Nazan Gökşen Tosun

  4. Division of Medical Biology, Department of Basic Medical Sciences, Hamidiye Faculty of Medicine, University of Health Sciences, Turkey, Istanbul, Turkey

    Şaban Tekin

  5. Experimental Medicine Application & Research Center, Validebag Research Park, University of Health Sciences, Istanbul, Turkey

    Şaban Tekin

  6. Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Tokat Gaziosmanpaşa University, Tokat, Turkey

    İsa Gökçe

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  1. Aykut Özgür
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Contributions

AÖ conceived the idea of the project. AÖ and AK designed the project. AÖ, AK and NGT performed all the experiments. AÖ, AK, NGT, ŞT and İG analyzed the data. AÖ created the first draft of the manuscript which was edited by all the authors.

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Correspondence to Aykut Özgür.

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Özgür, A., Kara, A., Gökşen Tosun, N. et al. Debio-0932, a second generation oral Hsp90 inhibitor, induces apoptosis in MCF-7 and MDA-MB-231 cell lines. Mol Biol Rep 48, 3439–3449 (2021). https://doi.org/10.1007/s11033-021-06392-z

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  • DOI: https://doi.org/10.1007/s11033-021-06392-z

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