Skip to main content
Log in

Preliminary evaluation and in vitro cytotoxicity studies of [131I]I-trastuzumab in HER2 expressing ovarian cancer cells

  • Published:
Journal of Radioanalytical and Nuclear Chemistry Aims and scope Submit manuscript

Abstract

As trastuzumab is known to target the human epidermal growth factor receptor type (HER2), the potential of [131I]I-trastuzumab as a radioimmunotherapy agent was evaluated in vitro and in vivo for HER2-overexpressing ovarian cancer cells (SKOV-3). [131I]I-trastuzumab showed promising in vitro properties and high tumor uptake in SKOV-3 xenografts. Its cellular toxicity was dose- and time-dependent, and it retained in the SKOV-3 cells in the G2/M phase of cell cycle. The mode of cell death was predominantly by apoptosis. These results demonstrate the potential of [131I]I-trastuzumab for further therapeutic evaluation in HER2-overexpressing ovarian cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Koshiyama M, Matsumura N, Konishi I (2017) Subtypes of Ovarian Cancer and Ovarian Cancer Screening. Diagnostics (Basel) 7(1):12. doi:https://doi.org/10.3390/diagnostics7010012

    Article  CAS  Google Scholar 

  2. Bisch SP, Sugimoto A, Prefontaine M, Bertrand M, Gawlik C, Welch S, McGee J (2018) Treatment Tolerance and Side Effects of Intraperitoneal Carboplatin and Dose-Dense Intravenous Paclitaxel in Ovarian Cancer. J Obstet Gynaecol Can 40(10):1283–1287e1281. doi:https://doi.org/10.1016/j.jogc.2018.01.028

    Article  PubMed  Google Scholar 

  3. Thibault B, Castells M, Delord JP, Couderc B (2014) Ovarian cancer microenvironment: implications for cancer dissemination and chemoresistance acquisition. Cancer Metastasis Rev 33(1):17–39. doi:https://doi.org/10.1007/s10555-013-9456-2

    Article  CAS  PubMed  Google Scholar 

  4. Coleridge SL, Bryant A, Kehoe S, Morrison J (2021) Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer. Cochrane Database Syst Rev 2:CD005343. doi:https://doi.org/10.1002/14651858.CD005343.pub5

    Article  PubMed  Google Scholar 

  5. Dogan I, Cumaoglu A, Aricioglu A, Ekmekci A (2011) Inhibition of ErbB2 by herceptin reduces viability and survival, induces apoptosis and oxidative stress in Calu-3 cell line. Mol Cell Biochem 347(1–2):41–51. doi:https://doi.org/10.1007/s11010-010-0610-7

    Article  CAS  PubMed  Google Scholar 

  6. Pauletti G, Godolphin W, Press MF, Slamon DJ (1996) Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. Oncogene 13(1):63–72

    CAS  PubMed  Google Scholar 

  7. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137. doi:https://doi.org/10.1038/35052073

    Article  CAS  PubMed  Google Scholar 

  8. Henson ES, Hu X, Gibson SB (2006) Herceptin sensitizes ErbB2-overexpressing cells to apoptosis by reducing antiapoptotic Mcl-1 expression. Clin Cancer Res 12(3 Pt 1):845–853. doi:https://doi.org/10.1158/1078-0432.CCR-05-0754

    Article  CAS  PubMed  Google Scholar 

  9. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15(5):429–440. doi:https://doi.org/10.1016/j.ccr.2009.03.020

    Article  CAS  PubMed  Google Scholar 

  10. Elizabeth S, Henson XH, Spencer B, Gibson (2006) Herceptin Sensitizes ErbB2-Overexpressing Cells to Apoptosisby Reducing Antiapoptotic Mcl-1 Expression Cancer Therapy. Clinical

  11. Chao WR, Lee MY, Lin WL, Chen CK, Lin JC, Koo CL, Sheu GT, Han CP (2014) HER2 amplification and overexpression are significantly correlated in mucinous epithelial ovarian cancer. Hum Pathol 45(4):810–816. doi:https://doi.org/10.1016/j.humpath.2013.11.016

    Article  CAS  PubMed  Google Scholar 

  12. Dominguez-Rios R, Sanchez-Ramirez DR, Ruiz-Saray K, Oceguera-Basurto PE, Almada M, Juarez J, Zepeda-Moreno A, Del Toro-Arreola A, Topete A, Daneri-Navarro A (2019) Cisplatin-loaded PLGA nanoparticles for HER2 targeted ovarian cancer therapy. Colloids Surf B Biointerfaces 178:199–207. doi:https://doi.org/10.1016/j.colsurfb.2019.03.011

    Article  CAS  PubMed  Google Scholar 

  13. Hellstrom I, Goodman G, Pullman J, Yang Y, Hellstrom KE (2001) Overexpression of HER-2 in ovarian carcinomas. Cancer Res 61(6):2420–2423

    CAS  PubMed  Google Scholar 

  14. Chung YW, Kim S, Hong JH, Lee JK, Lee NW, Lee YS, Song JY (2019) Overexpression of HER2/HER3 and clinical feature of ovarian cancer. J Gynecol Oncol 30(5):e75. doi:https://doi.org/10.3802/jgo.2019.30.e75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kameswaran M, Gota V, Ambade R, Gupta S, Dash A (2017) Preparation and preclinical evaluation of 131 I-trastuzumab for breast cancer. J Label Comp Radiopharm 60(1):12–19. doi:https://doi.org/10.1002/jlcr.3465

    Article  CAS  Google Scholar 

  16. D’Huyvetter M, De Vos J, Caveliers V, Vaneycken I, Heemskerk J, Duhoux FP, Fontaine C, Vanhoeij M, Windhorst AD, van der Aa F, Hendrikse NH, Eersels JLE, Everaert H, Gykiere P, Devoogdt N, Raes G, Lahoutte T, Keyaerts M (2020) Phase I trial of 131I-GMIB-Anti-HER2-VHH1, a new promising candidate for HER2-targeted radionuclide therapy in breast cancer patients. J Nucl Med. doi:https://doi.org/10.2967/jnumed.120.255679

    Article  PubMed  Google Scholar 

  17. Delord JP, Allal C, Canal M, Mery E, Rochaix P, Hennebelle I, Pradines A, Chatelut E, Bugat R, Guichard S, Canal P (2005) Selective inhibition of HER2 inhibits AKT signal transduction and prolongs disease-free survival in a micrometastasis model of ovarian carcinoma. Ann Oncol 16(12):1889–1897. doi:https://doi.org/10.1093/annonc/mdi405

    Article  CAS  PubMed  Google Scholar 

  18. Wilken JA, Webster KT, Maihle NJ (2010) Trastuzumab Sensitizes Ovarian Cancer Cells to EGFR-targeted Therapeutics. J Ovarian Res 3:7. doi:https://doi.org/10.1186/1757-2215-3-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mukherji M, Brill LM, Ficarro SB, Hampton GM, Schultz PG (2006) A phosphoproteomic analysis of the ErbB2 receptor tyrosine kinase signaling pathways. Biochemistry 45(51):15529–15540. doi:https://doi.org/10.1021/bi060971c

    Article  CAS  PubMed  Google Scholar 

  20. Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR (2003) Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol 21(2):283–290. doi:https://doi.org/10.1200/JCO.2003.10.104

    Article  CAS  PubMed  Google Scholar 

  21. McAlpine JN, Wiegand KC, Vang R, Ronnett BM, Adamiak A, Kobel M, Kalloger SE, Swenerton KD, Huntsman DG, Gilks CB, Miller DM (2009) HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy. BMC Cancer 9:433. doi:https://doi.org/10.1186/1471-2407-9-433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Larson SM, Carrasquillo JA, Cheung NK, Press OW (2015) Radioimmunotherapy of human tumours. Nat Rev Cancer 15(6):347–360. doi:https://doi.org/10.1038/nrc3925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Aghevlian S, Boyle AJ, Reilly RM (2017) Radioimmunotherapy of cancer with high linear energy transfer (LET) radiation delivered by radionuclides emitting alpha-particles or Auger electrons. Adv Drug Deliv Rev 109:102–118. doi:https://doi.org/10.1016/j.addr.2015.12.003

    Article  CAS  PubMed  Google Scholar 

  24. D’Huyvetter M, Vincke C, Xavier C, Aerts A, Impens N, Baatout S, De Raeve H, Muyldermans S, Caveliers V, Devoogdt N, Lahoutte T (2014) Targeted radionuclide therapy with A 177Lu-labeled anti-HER2 nanobody. Theranostics 4(7):708–720. doi:https://doi.org/10.7150/thno.8156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bhusari P, Vatsa R, Singh G, Parmar M, Bal A, Dhawan DK, Mittal BR, Shukla J (2017) Development of 177Lu-trastuzumab for radioimmunotherapy of HER2 expressing breast cancer and its feasibility assessment in breast cancer patients. Int J Cancer 140(4):938–947. doi:https://doi.org/10.1002/ijc.30500

    Article  CAS  PubMed  Google Scholar 

  26. Luo TY, Cheng PC, Chiang PF, Chuang TW, Yeh CH, Lin WJ (2015) 188Re-HYNIC-trastuzumab enhances the effect of apoptosis induced by trastuzumab in HER2-overexpressing breast cancer cells. Ann Nucl Med 29(1):52–62. doi:https://doi.org/10.1007/s12149-014-0908-8

    Article  CAS  PubMed  Google Scholar 

  27. Abbas N, Bruland OS, Brevik EM, Dahle J (2012) Preclinical evaluation of 227Th-labeled and 177Lu-labeled trastuzumab in mice with HER-2-positive ovarian cancer xenografts. Nucl Med Commun 33(8):838–847. doi:https://doi.org/10.1097/MNM.0b013e328354df7c

    Article  CAS  PubMed  Google Scholar 

  28. Nagarajah J, Janssen M, Hetkamp P, Jentzen W (2017) Iodine Symporter Targeting with 124I/131I Theranostics. J Nucl Med 58(Suppl 2):34S–38S. doi:https://doi.org/10.2967/jnumed.116.186866

    Article  CAS  PubMed  Google Scholar 

  29. Lin J, Luo RC, Li AM, Zhang JY, Lu CW, Yan X (2005) Killing effect of 131I-Herceptin on breast cancer cell lines in vitro. Di Yi Jun Yi Da Xue Xue Bao 25(6):663–666

    CAS  PubMed  Google Scholar 

  30. Fan YX, Luo RC, Fang YX, Yan X, Lu CW (2006) Effects of interferon-gamma on Her-2/neu expression and antitumor activity of 131I-Herceptin in breast cancer cell lines. Ai Zheng 25(4):443–446

    CAS  PubMed  Google Scholar 

  31. Gajria D, Chandarlapaty S (2011) HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther 11(2):263–275. doi:https://doi.org/10.1586/era.10.226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, Xiong Y, Tseng LM, Li SH, Ding Z, Sahin AA, Esteva FJ, Hortobagyi GN, Yu D (2011) Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 17(4):461–469. doi:https://doi.org/10.1038/nm.2309

    Article  CAS  PubMed  Google Scholar 

  33. Sato N, Mizumoto K, Nakamura M, Ueno H, Minamishima YA, Farber JL, Tanaka M (2000) A possible role for centrosome overduplication in radiation-induced cell death. Oncogene 19(46):5281–5290. doi:https://doi.org/10.1038/sj.onc.1203902

    Article  CAS  PubMed  Google Scholar 

  34. Vakifahmetoglu H, Olsson M, Zhivotovsky B (2008) Death through a tragedy: mitotic catastrophe. Cell Death Differ 15(7):1153–1162. doi:https://doi.org/10.1038/cdd.2008.47

    Article  CAS  PubMed  Google Scholar 

  35. Schmitt CA (2007) Cellular senescence and cancer treatment. Biochim Biophys Acta 1775(1):5–20. doi:https://doi.org/10.1016/j.bbcan.2006.08.005

    Article  CAS  PubMed  Google Scholar 

  36. Firestone RB (1999) Table of Isotopes. Wiley. 8 edn.doi:https://doi.org/10.1002/bbpc.19870910459

    Article  Google Scholar 

  37. Gupta S, Batra S, Jain M (2014) Antibody labeling with radioiodine and radiometals. Methods in molecular biology. (Clifton NJ) 1141:147–157. doi:https://doi.org/10.1007/978-1-4939-0363-4_9

    Article  CAS  Google Scholar 

  38. Lindmo T, Boven E, Cuttitta F, Fedorko J, Bunn PA Jr (1984) Determination of the immunoreactive fraction of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess. J Immunol Methods 72(1):77–89. doi:https://doi.org/10.1016/0022-1759(84)90435-6

    Article  CAS  PubMed  Google Scholar 

  39. Zhou Z, Chitneni SK, Devoogdt N, Zalutsky MR, Vaidyanathan G (2018) Fluorine-18 labeling of an anti-HER2 VHH using a residualizing prosthetic group via a strain-promoted click reaction: Chemistry and preliminary evaluation. Bioorg Med Chem 26(8):1939–1949

    Article  CAS  Google Scholar 

  40. Vaidyanathan G, McDougald D, Choi J, Pruszynski M, Koumarianou E, Zhou Z, Zalutsky MR (2016) N-Succinimidyl 3-((4-(4-[(18)F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ([(18)F]SFBTMGMB): a residualizing label for (18)F-labeling of internalizing biomolecules. Org Biomol Chem 14(4):1261–1271. doi:https://doi.org/10.1039/c5ob02258d

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yong KJ, Milenic DE, Baidoo KE, Brechbiel MW (2013) Sensitization of tumor to ²¹²Pb radioimmunotherapy by gemcitabine involves initial abrogation of G2 arrest and blocked DNA damage repair by interference with Rad51. Int J Radiat Oncol Biol Phys 85(4):1119–1126. doi:https://doi.org/10.1016/j.ijrobp.2012.09.015

    Article  CAS  PubMed  Google Scholar 

  42. Yong KJ, Milenic DE, Baidoo KE, Brechbiel MW (2012) (212)Pb-radioimmunotherapy induces G(2) cell-cycle arrest and delays DNA damage repair in tumor xenografts in a model for disseminated intraperitoneal disease. Mol Cancer Ther 11(3):639–648. doi:https://doi.org/10.1158/1535-7163.MCT-11-0671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nicolini F, Burmistrova O, Marrero MT, Torres F, Hernández C, Quintana J, Estévez F (2014) Induction of G2/M phase arrest and apoptosis by the flavonoid tamarixetin on human leukemia cells. Mol Carcinog 53(12):939–950. doi:https://doi.org/10.1002/mc.22055

    Article  CAS  PubMed  Google Scholar 

  44. Wang C, Wang J, Jiang H, Zhu M, Chen B, Bao W (2011) In vitro study on apoptosis induced by strontium-89 in human breast carcinoma cell line. J Biomed Biotechnol 2011:541487–541487. doi:https://doi.org/10.1155/2011/541487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Eriksson D, Blomberg J, Lindgren T, Löfroth PO, Johansson L, Riklund K, Stigbrand T (2008) Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells. Cancer Biother Radiopharm 23(5):541–549. doi:https://doi.org/10.1089/cbr.2008.0471

    Article  CAS  PubMed  Google Scholar 

  46. Wardman P (2007) Chemical radiosensitizers for use in radiotherapy. Clin Oncol (R Coll Radiol) 19(6):397–417. doi:https://doi.org/10.1016/j.clon.2007.03.010

    Article  CAS  Google Scholar 

  47. Topham CH, Taylor SS (2013) Mitosis and apoptosis: how is the balance set? Curr Opin Cell Biol 25(6):780–785. doi:https://doi.org/10.1016/j.ceb.2013.07.003

    Article  CAS  PubMed  Google Scholar 

  48. Friesen C, Fulda S, Debatin KM (1999) Cytotoxic drugs and the CD95 pathway. Leukemia 13(11):1854–1858. doi:https://doi.org/10.1038/sj.leu.2401333

    Article  CAS  PubMed  Google Scholar 

  49. Friesen C, Lubatschofski A, Kotzerke J, Buchmann I, Reske SN, Debatin KM (2003) Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells. Eur J Nucl Med Mol Imaging 30(9):1251–1261. doi:https://doi.org/10.1007/s00259-003-1216-z

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by the National Natural Science Foundation of China (grant no. 21976167, 21906155 and 21701155), the CAEP Innovation and Development Foundation (grant no. CX20200003), the Key R&D Project of Sichuan Science and Technology Program (grant no. 2020YFS0030 and 2019ZDZX0012) and Nuclear Energy Development Project of State Administration of Science, Technology, and Industry for National Defense (grant no. 20201192–1).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jing Wang.

Ethics declarations

Conflict of interest

There is no conflict of interest.

Credit author statement: Hao Deng

Conceptualization, Methodology, Investigation, Software, Visualization, Writing original draft preparation, Writing Reviewing and Editing.

Wei Liu

Data curation, Investigation, Validation.

Xia Yang

Investigation, Visualization.

Kehong Li

Investigation, Visualization.

Wei Liao

Resources, Investigation.

Peng Zhao

Software, Data Curation, Investigation.

Yuchuan Yang

Investigation.

Hongyuan Wei

Supervision.

Jing Wang

Supervision, Project administration, Writing-Reviewing and Editing.

Yue Chen

Supervision.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Deng, H., Liu, W., Yang, X. et al. Preliminary evaluation and in vitro cytotoxicity studies of [131I]I-trastuzumab in HER2 expressing ovarian cancer cells. J Radioanal Nucl Chem 331, 2451–2460 (2022). https://doi.org/10.1007/s10967-022-08329-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10967-022-08329-7

Keywords

Navigation