Open Access Journal Article

Targeted intracellular delivery of BH3 mimetic peptide inhibits BCL-2 activity and prevents breast cancer development

by Zhengdong Yuan a ,  Yiwen Zhang a ,  Xuena Yang a  and  Hai Qin b,*
a
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
b
Department of Clinical Laboratory, Beijing Jishuitan Hospital Guizhou Hospital, Guiyang, 550014, China
*
Author to whom correspondence should be addressed.
CI  2024, 38; 3(2), 38; https://doi.org/10.58567/ci03020006
Received: 6 January 2024 / Accepted: 22 March 2024 / Published Online: 2 April 2024
View Full-Text
Download PDF

Abstract

Breast cancer, as a malignant tumor with easy metastasis and poor prognosis, threatens the health of women around the world. Increasing studies have shown that the Bcl-2 family of apoptosis-related proteins is often expressed abnormally in breast cancer. The Bcl-2 homology 3 (BH3) mimetic peptide can bind and neutralize Bcl-2, preventing its binding to the apoptosis "effector" proteins Bak and Bax, thereby promoting the apoptosis process. However, there is a lack of effective intracellular delivery system for BH3 to exert its biological activity. Therefore, this study utilized an activatable supercharged polypeptide (ASCP) tumor-targeted delivery platform based on pH and protease response to achieve the targeted release of BH3 at the tumor site. Ultimately, intracellular delivery of BH3 was achieved and induced apoptosis of breast tumor cells, preventing the development of breast cancer.

Keywords: Breast cancer; B-cell lymphoma 2 (Bcl-2) family; BH3; activatable supercharged polypeptide; peptide delivery;
Copyright: © 2024 by Yuan, Zhang, Yang and Qin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (Creative Commons Attribution 4.0 International License). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Share and Cite

ACS Style
Yuan, Z.; Zhang, Y.; Yang, X.; Qin, H. Targeted intracellular delivery of BH3 mimetic peptide inhibits BCL-2 activity and prevents breast cancer development. Cancer Insight, 2024, 3, 38. https://doi.org/10.58567/ci03020006
AMA Style
Yuan Z, Zhang Y, Yang X, Qin H. Targeted intracellular delivery of BH3 mimetic peptide inhibits BCL-2 activity and prevents breast cancer development. Cancer Insight; 2024, 3(2):38. https://doi.org/10.58567/ci03020006
Chicago/Turabian Style
Yuan, Zhengdong; Zhang, Yiwen; Yang, Xuena; Qin, Hai 2024. "Targeted intracellular delivery of BH3 mimetic peptide inhibits BCL-2 activity and prevents breast cancer development" Cancer Insight 3, no.2:38. https://doi.org/10.58567/ci03020006
APA style
Yuan, Z., Zhang, Y., Yang, X., & Qin, H. (2024). Targeted intracellular delivery of BH3 mimetic peptide inhibits BCL-2 activity and prevents breast cancer development. Cancer Insight, 3(2), 38. https://doi.org/10.58567/ci03020006

Article Metrics

Article Access Statistics

References

  1. D. Merino, S. W. Lok, J. E. Visvader, G. J. Lindeman. (2016). Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer. Oncogene 35, 1877-1887. https://doi.org/10.1038/onc.2015.287
  2. N. Harbeck, M. Gnant. (2017). Breast cancer. Lancet 389, 1134-1150. https://doi.org/10.1016/S0140-6736(16)31891-8
  3. Xuerong Wang et al. (2021). Progress of Breast Cancer basic research in China. International Journal of Biological Sciences 17(8), 2069-2079. https://doi.org/10.7150/ijbs.60631
  4. R. W. Johnstone, A. A. Ruefli, S. W. Lowe. (2002). Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153-164. https://doi.org/10.1016/S0092-8674(02)00625-6
  5. T. Miyashita, J. C. Reed. (1993). Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81, 151-157. https://doi.org/10.1182/blood.V81.1.151.151
  6. E. Wesarg et al. (2007). Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer. Int J Cancer 121, 2387-2394. https://doi.org/10.1002/ijc.22977
  7. G. Gasparini et al. (1995). Expression of bcl-2 protein predicts efficacy of adjuvant treatments in operable node-positive breast cancer. Clin Cancer Res 1, 189-198.
  8. D. Westphal, G. Dewson, P. E. Czabotar, R. M. Kluck. (2011). Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta 1813, 521-531. https://doi.org/10.1016/j.bbamcr.2010.12.019
  9. T. T. Renault, S. Manon. (2011). Bax: Addressed to kill. Biochimie 93, 1379-1391. https://doi.org/10.1016/j.biochi.2011.05.013
  10. G. Hacker, A. Weber. (2007). BH3-only proteins trigger cytochrome c release, but how? Arch Biochem Biophys 462, 150-155. https://doi.org/10.1016/j.abb.2006.12.022
  11. C. M. Adams, S. Clark-Garvey, P. Porcu, C. M. Eischen. (2018). Targeting the Bcl-2 Family in B Cell Lymphoma. Front Oncol 8, 636. https://doi.org/10.3389/fonc.2018.00636
  12. R. Li et al. (2007). Targeting antiapoptotic Bcl-2 family members with cell-permeable BH3 peptides induces apoptosis signaling and death in head and neck squamous cell carcinoma cells. Neoplasia 9, 801-811. https://doi.org/10.1593/neo.07394
  13. S. J. Dawson et al. (2010). BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer 103, 668-675. https://doi.org/10.1038/sj.bjc.6605736
  14. S. R. Oakes et al. (2012). Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737. Proc Natl Acad Sci U S A 109, 2766-2771. https://doi.org/10.1073/pnas.1104778108
  15. A. J. Souers et al. (2013). ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19, 202-208. https://doi.org/10.1038/nm.3048
  16. D. Merino et al. (2018). BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines. Cancer Cell 34, 879-891. https://doi.org/10.1016/j.ccell.2018.11.004
  17. A. A. Mateos-Chavez et al. (2019). Live Attenuated Salmonella enterica Expressing and Releasing Cell-Permeable Bax BH3 Peptide Through the MisL Autotransporter System Elicits Antitumor Activity in a Murine Xenograft Model of Human B Non-hodgkin's Lymphoma. Front Immunol 10, 2562. https://doi.org/10.3389/fimmu.2019.02562
  18. Y. F. Yang et al. (2023). A Versatile Platform for the Tumor-Targeted Intracellular Delivery of Peptides, Proteins, and siRNA. Adv Funct Mater 33. https://doi.org/10.1002/adfm.202301011
  19. M. Jung, S. Ghamrawi, E. Y. Du, J. J. (2022). Gooding, M. Kavallaris, Advances in 3D Bioprinting for Cancer Biology and Precision Medicine: From Matrix Design to Application. Adv Healthc Mater 11, e2200690. https://doi.org/10.1002/adhm.202200690
  20. E. M. Kim et al. (2017). The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins. Cancer Res 77, 3092-3100. https://doi.org/10.1158/0008-5472.CAN-16-2098
  21. M. H. Kang, C. P. Reynolds. (2009). Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15, 1126-1132. https://doi.org/10.1158/1078-0432.CCR-08-0144
  22. C. Billard. (2012). Design of novel BH3 mimetics for the treatment of chronic lymphocytic leukemia. Leukemia 26, 2032-2038. https://doi.org/10.1038/leu.2012.88
  23. C. Curtis et al. (2012). The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346-352. https://doi.org/10.1038/nature10983
  24. P. E. Czabotar, G. Lessene, A. Strasser, J. M. Adams. (2014). Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15, 49-63. https://doi.org/10.1038/nrm3722
  25. M. Q. Baggstrom et al. (2011). A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. J Thorac Oncol 6, 1757-1760. https://doi.org/10.1097/JTO.0b013e31822e2941
  26. M. A. Anderson, D. (2014). Huang, A. Roberts, Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol 51, 219-227. https://doi.org/10.1053/j.seminhematol.2014.05.008
  27. M. Chiper, K. Niederreither, G. Zuber. (2018). Transduction Methods for Cytosolic Delivery of Proteins and Bioconjugates into Living Cells. Adv Healthc Mater 7, e1701040. https://doi.org/10.1002/adhm.201701040
  28. S. Du, S. S. Liew, L. Li, S. Q. Yao. (2018). Bypassing Endocytosis: Direct Cytosolic Delivery of Proteins. J Am Chem Soc 140, 15986-15996. https://doi.org/10.1021/jacs.8b06584
  29. J. A. Zuris et al. (2015). Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat Biotechnol 33, 73-80. https://doi.org/10.1038/nbt.3081
  30. I. Ekladious, Y. L. Colson, M. W. Grinstaff. (2019). Polymer-drug conjugate therapeutics: advances, insights and prospects. Nat Rev Drug Discov 18, 273-294. https://doi.org/10.1038/s41573-018-0005-0
  31. J. Lv, Q. Fan, H. Wang, Y. Cheng. (2019). Polymers for cytosolic protein delivery. Biomaterials 218, 119358. https://doi.org/10.1016/j.biomaterials.2019.119358
  32. S. Florinas et al. (2016). A Nanoparticle Platform To Evaluate Bioconjugation and Receptor-Mediated Cell Uptake Using Cross-Linked Polyion Complex Micelles Bearing Antibody Fragments. Biomacromolecules 17, 1818-1833. https://doi.org/10.1021/acs.biomac.6b00239
  33. S. Jafari, S. Maleki Dizaj, K. Adibkia. (2015). Cell-penetrating peptides and their analogues as novel nanocarriers for drug delivery. Bioimpacts 5, 103-111. https://doi.org/10.15171/bi.2015.10
  34. D. B. Thompson, R. Villasenor, B. M. Dorr, M. Zerial, D. R. Liu. (2012). Cellular uptake mechanisms and endosomal trafficking of supercharged proteins. Chem Biol 19, 831-843. https://doi.org/10.1016/j.chembiol.2012.06.014
  35. Q. Wang et al. (2021). Cytosolic Protein Delivery for Intracellular Antigen Targeting Using Supercharged Polypeptide Delivery Platform. Nano Lett 21, 6022-6030. https://doi.org/10.1021/acs.nanolett.1c01190